Background

The prevalence of nosocomial and community-acquired multidrug-resistant (MDR) bacterial infections with limited effective treatment options is on the rise worldwide (CDC 2013; CDDEP 2015). Notable examples include the increase in the incidence of methicillin-resistant Staphylococcus aureus (MRSA), emergence of MRSA clinical isolates insensitive to vancomycin (CDC 2013; Iyamba et al. 2014; Thati et al. 2011; Loomba et al. 2010), and high prevalence of carbapenem-resistant Enterobacteriaceae (CRE) infections. This is worsened by the fact that most of these resistant infections have no commendable treatment alternatives (Livermore et al. 2011; Nordmann et al. 2011, 2012). With such consequences, antimicrobial resistance (AMR) has resulted into increased morbidity and mortality to would-be unthreatening bacterial infections. Therefore, AMR has emerged as one of the leading threats to human and animal health (CDC 2013; Lowy 2003). A number of factors have been implicated as drivers of AMR. The most common ones include biofilms, overuse of antibiotics, irrational prescription of antibiotics, and the use of antibiotics in livestock to promote growth (Hausner and Wuertz 1999; Høiby et al. 2010; Economou and Gousia 2015; Warnes et al. 2012; Ceri et al. 1999). Overconsumption of antibiotics presents selective pressures to bacterial population where some adapt by developing molecular resistance mechanisms such as antibiotic resistance-encoding genes (Queenan and Bush 2007: Brody et al. 2008; Punina et al. 2015; Perez et al. 2007; Gulmez et al. 2008; Pfeifer et al. 2012; Poirel and Nordmann 2006; Perez et al. 2007), hence evolving to form resistant strains. A number of studies have documented the molecular mechanisms of AMR; these are summarized in Table 1 and Figs. 1 and 2.

Table 1 Molecular mechanisms of antibiotic resistance
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Fig. 1
figure 1

Molecular mechanisms of antibiotic resistance. (Addae et al. 2014) Acquisition of chromosomal and plasmid antibiotics resistance genes (gene-encoding enzymes which (a) hydrolyze antibiotics and (b) modify drugs). (Ali et al. 2011) Acquisition of antibiotics efflux pump genes. (Alves et al. 2017) Mutation in the gene encoding a vital target protein such (PBP) so that an altered drug target is expressed. (Ansari et al. 2014) Mutation in gene expressing OMP so that a truncated OMP is produced or there is downregulation of OMP

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Fig. 2
figure 2

Mechanisms of bacterial resistance to antibiotics and nanoparticles and how to combat them using nanotechnology. Acquisition of (Addae et al. 2014) chromosomal or plasmid genetic resistance determinants which encode for drug hydrolyzing enzymes, efflux pumps for both (Ali et al. 2011) drugs, and (Alves et al. 2017) NPs. (Ansari et al. 2014) Mutation in the OMP genes to express modified OMP; (Anwar et al. 2018) downregulation of drug channels (OMP); (Asadishad et al. 2012) drug nanocarriers to shield drugs from the inactivation of enzymes, conjugating drugs to NPs and nanobodies; (Asgarali et al. 2009) NPs to NPs with antibacterial activity such as antibodies, Ag, CuO, and chitosan, among others, to attain multiple modes of action synergistic antibacterial activity; and (Bansod et al. 2015) capping of nanomaterials with bacterial adhesin secretion inhibitors

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Furthermore, leading pharmaceutical companies have shut down their antibiotics research and development programs due to the fact that antibiotics are less lucrative than other drugs used in the treatment of protracted ailments. This is mainly because (a) most new antibiotic generations are inaccessible, prohibited, shelved and used as last resort antibiotics ostensibly to protect them against resistance, and (b) they are used for a short period of time, and they become obsolete due to emergence of resistance limiting the initial return on investment (Nature Biotechnology Volume 36 Number 7 July 2018; Spellberg et al. 2004; Power and Schering–Plough Corporation 2006). Therefore, based on the present rate of antibiotic production and approvals, it is projected that by 2050, up to 10 million people could die annually due to MDR superbug infections (Nature Biotechnology Volume 36 Number 7 July 2018). Thus, this necessitates development of novel alternatives to antibiotics.

One of the promising strategies to control antibiotic resistance is the use of nanoparticle (NP) therapeutics, nanostructured coating of indwelling and other medical devices in addition to nanodrug delivery systems. Nanoparticles are materials where at least one dimension lies between 1 and 100 nm (Khan et al. 2017). Nanoscale materials have garnered attention since they occupy very little space but with a very large surface area to volume. Reducing material to nanoscale increases the surface area to volume ratio, and this affords the resultant NPs very high versatility, solubility, chemical reactivity, and different morphologies with different mechanisms of action (Padmavathy and Vijayaraghavan 2008; Simon-Deckers et al. 2009). Various types of NPs presently accessible and under fabrication include inorganic metals, organic polymers, organic natural compounds, and nanostructured materials. Diverse engineering systems are required to fabricate these nanoparticle types, and each type can exhibit a variety of biomedical functions via different modes of action. NPs have demonstrated potent antibacterial activity in ex vivo, in vivo, and in vitro experiments. Thus, these NPs have attracted the attention in the health sector to be used as alternative or co-antimicrobial agents, nanoantibiotics delivery systems, and nanostructured coatings owing to their undisputed bactericide ability mediated by different mechanisms (Simon-Deckers et al. 2009).

Inorganic metal NPs such as silver, gold, zinc, copper, and titanium and organic NPs such as chitosan have been experimented as substitutes to antibiotics and conventional disinfectants. Notable examples include the use of NPs to avert catheter-associated infections and biofilm formation and the use of NPs in antimicrobial wound dressing and coatings (Padmavathy and Vijayaraghavan 2008; Simon-Deckers et al. 2009; Li et al. 2011; Ren et al. 2009; Meghana et al. 2015; Lai et al. 2015; Jahnke et al. 2016; Shahverdi et al. 2007; Ivask et al. 2014; 35. Pérez-Díaz et al. 2015; Cui et al. 2013; Ramalingam et al. 2016; McQuillan and Shaw 2014; Ali et al. 2011). However, the emergence of resistance to Ag NPs and other heavy metals in Escherichia coli threatens the use of metal NPs as substitutes to antibiotics (Panáček et al. 2017; Tajkarimi et al. 2017). This resistance is attributed to the (a) acquisition and upregulation of efflux pumps for Ag NPs and other metal nanomaterials; (b) enzymatic alterations of nanomaterials such as oxidation, reduction, methylation, and demethylation; (c) gaining and overexpression of metal-binding proteins notably metallothionein, SmtA, chaperone CopZ, and SilE (Silver and Phoung 2005); (d) limiting entry of nanomaterials by mutation and suppression of expression of genes encoding the metal ion transmembrane proteins (Graves et al. 2015); and (e) extracellular secretion of flagellin adhesive protein that induce agglomeration of silver NPs (Tajkarimi et al. 2017). To achieve meaningful outcomes, attempts should be made to design nanotherapeutic agents with the capacity to circumvent the modes of resistance to heavy ionic and nanoscale metals in addition to the molecular mechanisms of resistance that have rendered conventional antibiotics obsolete. Therefore, the fabrication process of antibacterial nanomaterial should encompass strategies to overcome the emergence of resistance to the novel nanotherapeutic agents as well as shielding antibiotics from the various mechanisms of resistance.

Pathogen acquisition of AMR to a single therapeutic agent is not complex as resistance can be achieved through relatively simple genomic modifications (Fig. 2) (Tajkarimi et al. 2017). Therefore, antimicrobial combinatory strategy is the most promising approach to curb antimicrobial resistance (Asgarali et al. 2009). This may entail fabrication of nanocomposites through combination of antibiotics and nanomolecules with antibacterial activity, two or three nanosubstances, and loading antibiotics and NPs in nanodrug delivery systems (Fig. 2). Combinatory effects of NPs and antibiotics, two or more nanosubstances, will most likely evade bacterial antimicrobial resistance mechanisms, while nanodrug vehicles with antibacterial activity, such as silver NPs, copper NPs, chitosan NPs, among others, will not only protect antibiotics from the molecular mechanisms of resistance but will confer the nanodrug delivery system-antibiotics complex synergistic antibacterial effect; that is to say, conventional antibiotics will be re-potentiated by synergistic combination with NPs against MDR bacteria (Selvaraj et al. 2019). For example, nanodrug/antibiotic delivery platforms boost drug specificity and delivery, consequently reducing the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of antibiotics (Panáček et al. 2015). However, synergy is not a guarantee against the evolution of antimicrobial resistance, as a pleiotropic mutation can simply reverse the effects of synergistic treatments. Therefore, for effective nanomaterial-antibiotics combinatory approaches, nanomaterials should be designed to target bacterial pathways so that the evolution of bacterial resistance to nanomaterials compromises their resistance to several classes of antibiotics as observed in phage therapy experiments (Chan et al. 2016). Furthermore, nanodelivery systems enhance susceptibility of MDR or pan-drug-resistant (PDR) bacteria strains to antibiotics as they shield them from bacterial hydrolytic enzymes and they defeat resistance mechanisms such as impermeability to antibiotics due to alteration of the outer membrane porin proteins since the nanoantibiotic complex has a different configuration compared with the individual antibiotic (Fig. 2) (Hofmann et al. 2014: Li et al. 2012). Synergistic antibacterial effect may be achieved if the NPs conjugated to therapeutic agents to form a nanocarrier-antimicrobial complex also possess bactericide effects (Panáček et al. 2015). Furthermore, organic nanodelivery systems such as chitosan and liposome nanocarrier systems and inorganic drug nanovectors such as gold have been experimented in encapsulating and delivering of unstable antimicrobial agents such as bacteriophages, phytochemicals, peptides, and conventional antibiotics (Gao et al. 2018; Colonna et al. 2007; Hou et al. 2012; Burygin et al. 2009). Pomegranate rind extract (PGRE) has been proven to suppress secretion of bacterial flagellins (Asadishad et al. 2012). Therefore, approaches such as PGRE-mediated green synthesis and encapsulation will protect metal NPs from flagellin-induced aggregation.

On the other hand, inorganic NPs generated by the reduction of metal ions are non-biodegradable and hence can accumulate in the body organs, inducing harmful time-dosage-dependent cytotoxicity, while nanopolymers have exhibited biocompatibility since they are biodegradable. Biocompatibility of NPs determines their medical application as in vivo therapeutics, and drug delivery vehicles as biocompatible NPs are most likely to be safe in exhibiting selective toxicity to the target pathogens (Travan et al. 2009; Choi et al. 2010; Umashankari et al. 2012).

Therefore, this systematic review summarizes the current status of application of nanoparticles as antibacterial agents, antibiotics supplements, and drug delivery systems aimed at curbing antibiotic resistance. In addition, it discusses the success, future prospects, and limitations of nanotechnological solutions to control emergence and transmission of antibiotic-resistant bacterial infections.

Methods

Literature review emphatic

A comprehensive literature search of PubMed and BioMed Central databases from June 2018 to January 2019 was performed. The search keywords used were “use of nanotechnology to control antibiotic resistance” to extract articles published only in English encompassing all research papers regardless of the year of publication in an attempt to capture all published literature about the application of NPs as antibacterial therapeutic agents worldwide (Fig. 3).

Fig. 3
figure 3

Selection process of research articles for inclusion in this systematic review

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Criteria for article inclusion

Only full-text research articles and proceedings from the International Conference on Prevention and Infection Control with information concerning nanoparticles were included. Other parameters considered were the type of nanoparticles, methods used in preparation of nanoparticles, methods used in characterization of NPs and their physicochemical properties, target organisms, form of application, NPs’ exposure time, mechanism of action of NPs, level of NPs’ efficacy, and effective NP dose (Tables 2, 3, and 4). Review articles looking at applications of nanotechnology in medicine fell short of the inclusion criteria and were excluded.

Table 2 Inorganic nanoparticles used as antibacterial agents and methods of fabrication and characterization
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Table 3 Hybrid nanocomposites with bactericide activity and their methods of preparation and characterization
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Table 4 Organic nanomaterials used as bactericide agents or antibacterial agents delivery systems
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Data extraction

A database was created with several parameters that included the type of NPs used (inorganic, organic, and hybrid nanocomplex); methods used in the synthesis and characterization of NPs; physicochemical properties such size, morphology, and zeta potential; target organisms, form of application such as in vitro, in vivo, and ex vivo antibacterial activity; nanodrug delivery platforms; synergism of NPs and conventional antibiotics; cytotoxicity assays; duration of NP susceptibility experiments; mechanism of action of NPs; level of bactericidal effect of NPs; and the effective bactericide NP concentration.

Data analysis

Data analysis was performed using GraphPad Prism version 7.01. Comparisons of the efficacies and effective concentration between inorganic NPs, organic NPs, and nanohybrids were made using a one-way analysis of variance (ANOVA) followed by Tukey’s multiple comparisons test. Similarly, one-way ANOVA was performed to compare the efficacy of nanoparticles between bacterial planktons and biofilms. To minimize skewing of data, a study by Umashankari et al. (2012) which reported abnormally very high effective dose of 7.5 x 107μg/ml was excluded from the analysis (Table 2). A P value of ≤ 0.05 indicated substantial statistical variance.

Results

Literature search

The electronic literature search carried out between June 2018 and January 2019 generated a total of 166 articles; PubMed and BioMed Central databases generated 85 and 81 articles, respectively. Following the exclusion of 85 articles based on their titles, 81 articles were screened using abstracts, and of these, 21 articles fell short of the specified inclusion criteria. Finally, 60 full-text articles were accessed and reviewed, of which 49 full-text research articles fulfilled the inclusion guidelines for this systematic review (Fig. 3).

Inorganic nanoparticles

Out of the 49 articles included in this systematic review, 22 articles reported the use of nanoparticles generated from inorganic metal irons as antibacterial agents. Eight articles reported the use of silver NP (Umashankari et al. 2012; Palanisamy et al. 2014; Sowmya et al. 2018; Raman et al. 2017; Bansod et al. 2015; Rafińska et al. 2019; Reithofer et al. 2014; Singh et al. 2014); three articles reported use of titanium (Cheng et al. 2009; Senarathna et al. 2017; Ercan et al. 2011); and one article in each case reported the use of gold (Naz et al. 2013), zinc (Seil and Webster 2012), aluminum (Ansari et al. 2014), magnesium (He et al. 2016), cadmium (Salehi et al. 2014), and nanoshield (Michalikova et al. 2017). Two studies compared the antimicrobial activity of two metal nanomaterials independently, zinc and titanium (Khan et al. 2016) and gold and iron (Chatterjee et al. 2011). Other studies attempted to investigate the synergism of two metal NPs; one study in each case investigated the synergism of zinc and silver (Jafari et al. 2017), gold and copper (Addae et al. 2014), and gold and silver (Islam et al. 2017) NP cocktails (Table 2).

Inorganic-organic hybrid nanocomposites

Inorganic-organic nanohybrids are nanocomposites formed by conjugation of inorganic NPs to organic nanoscale or non-nanoscale polymers (de la Fuente and Grazu 2012). The literature search generated 15 research reports in which inorganic-organic nanohybrids were used. Eight studies reported the use of nanosilver-based polymers; thermoplastic polyurethane (TPU)-polydopamine (DA) silver nanopolymer (TPU-NS2.5) released silver ions with 100% antibacterial activity against Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus (MRSA) in in vitro assay and protected 100% of mice from MRSA-induced wound infections in in vivo studies and TPU-DA possessed no antibacterial activity (Liu et al. 2018). The bacterial activity of pegylated silver-coated single-walled carbon nanotubes (pSWCNT-Ag) and silver-coated single-walled carbon nanotubes (SWCNT-Ag) was compared. Both nanocomposites exhibited potent antibacterial activity against E. coli at concentrations of 50 and 62.5 μg/ml. For Salmonella enterica serovar typhimurium and Salmonella enterica serovar anatum, only pSWCNT-Ag at 62.5 μg/ml had potent antibacterial activity. Furthermore, at a concentration of 50 μg/ml pSWCNT-Ag and both 50 and 62.5 μg/ml, non-pegylated SWCNT-Ag had partial to no growth suppression effects on S. typhimurium and S. anatum (Park et al. 2018). In another study, polyhydroxyethyl methacrylate (PHEMA) was loaded with silver NPs. The hydrogel released silver NPs efficiently with in vitro and in vivo efficacy of 100% against E. coli and S. aureus infections in mice (Xu et al. 2018). Silver NPs were adsorbed on silicate platelet to form a stabilizing nanocarrier for silver NPs with 100% bactericide effect on E. coli, S. aureus, and S. typhimurium (Su et al. 2011). In another study, bone morphogenetic protein 2 (BMP-2) coupled-nanosilver-poly-DL-lactic-co-glycolic acid (PLGA) composite grafts were designed. They demonstrated 100% efficacy against vancomycin-resistant MRSA in vitro and in vivo (mice) assays (Zhenga et al. 2010). Silver NP-doped calcium phosphate-based ceramic-coating titanium prosthetic implants rescued 89% (8 out of 9) rabbits, while the control (calcium phosphate-based ceramic-coating titanium prosthetic implants) rescued 11% (1 out of 9) of the rabbits from MRSA bone infections (Kose et al. 2013). Two studies reported the synergism of the compounds within a nanohybrid. In one study, silver NPs conjugated to curcumin exhibited a combinatory antimicrobial effect of 100% on E. coli and P. aeruginosa (Alves et al. 2017), while gold NPs’ surface modified by polyelectrolyte (PAH) and silver NPs had a synergistic inhibitory effect of 100% on E. coli and Bacillus Calmette-Guérin (Zhou et al. 2012) (Table 3).

Regarding nanodrug delivery systems, two studies employed iron oxide NPs. Niemirowicz et al. (2015) designed a ceragenin-coated iron oxide magnetic NPs (MNP-CSA-13). Iron oxide magnetic NPs were used to deliver CSA-13 antimicrobial peptide. The CSA-13 exerted a 100% inhibitory activity of free-living and biofilm P. aeruginosa at a concentration of 10 μg/ml and 100 μg/ml, respectively. In the second study, Chemello et al. (2016) designed an iron oxide NPs-oxytetracyclin nanocarrier system. The nanodrug vector delivered the antibiotic effectively to the target zebrafish tissues infected with bacterial pathogens without exhibiting toxic effects to the host cells (Table 3).

One study in each case employed zinc, gold, bismuth, and cadmium-titanium NPs linked to other organic substances. Zinc oxide nanorods-graphene nanoplatelets (ZNGs) nanocomplex successfully eliminated 100% S. aureus and P. aeruginosa planktons and 96% and 50% of S. aureus and P. aeruginosa biofilms (Zanni et al. 2017). Anwar et al. (2018) functionalized pefloxacin using (dimethylamino) pyridine propylthioacetate-coated gold nanoparticles (DMAP-PTA). The latter and the former were inactive against E. coli. But after combining them, DMAP-PTA-pefloxacin nanohybrid achieved a bactericide effect of 100% on E. coli. Luo et al. (2013) used bismuth NPs as a vector to deliver polyclonal P. aeruginosa antibodies. The bismuth nanocarrier preserved the viability of the antibodies, and they exhibited antibacterial efficacy of 90% against MDR P. aeruginosa compared with 6% without the nanocarrier in vitro experiments. Cadmium tellurium (CdTe) and titanium oxide (TiO2)-CdTe-TiO2 nanocomposite capped with mercaptopropionic acid (MPA) and conjugated with semiconductor quantum dots (QDs) exhibited an antibacterial activity of 99.9% against E. coli and B. subtilis planktons and 60% against P. aeruginosa (Gholap et al. 2013). Inorganic-organic Ormostamp surfaces with nanopillar arrays fabricated using UV nanoreplication technology completely inhibited the growth of S. aureus (Wu et al. 2018) (Table 3).

Organic nanomolecules

The search yielded 12 articles reporting the use of nanoorganic molecules as antibacterial agents or antimicrobial nanocarriers. Nine studies investigated the use of nanoorganic compounds as drug delivery system. Nanoemulsions enclosing Cymbopogon flexuosus (Da Silva Gündel et al. 2018), solid lipid NPs loaded with Eugenia caryophyllata essential oil (SLN-EO) (Fazly Bazzaz et al. 2018), chitosan NP holding ciprofloxacin (Cipro/CSNPs) (Marei et al. 2018), methacrylate nanocarrier delivery system packaging clavanin A (Saude et al. 2014), oleic acid (OA)-monomethoxy polyethylene glycol (mPEG) nanocarrier loaded with vancomycin (Omolo et al. 2017), imipenem/cilastatin loaded poly Ɛ-caprolactone (PCL), and polylactide-co-glycolide (PLGA) nanocapsules (Shaaban et al. 2017) exhibited enhanced antibacterial activity against antibiotic-resistant and non-resistant clinical isolates. For instance, these nanodelivery systems enhanced the efficacy of imipenem and vancomycin to 74–78.4% and 86.8%–90.5% against imipenem-resistant isolates (K. pneumoniae and P. aeruginosa) and MRSA, respectively, while graphene oxide (GO) nanosheet carrier had no augmentation on bactericide effect of sulfamethoxazole (SMZ) (Zou et al. 2016). Two studies applied nanocarriers coated with pro-inflammatory molecules to promote cell-mediated immune response. Monocyte chemoattractant protein-1 (MCP-1) carrying interleukin-12 p70 (IL-12p70), nanocoatings on orthopedic implants (Li et al. 2010), and multilayer polypeptide nanoscale coatings loaded with IL-12 (Li et al. 2009) successfully provoked the body’s natural immunity against open fracture S. aureus infections in rat models (Table 4).

Three research articles reported the use of nanoorganic compounds as bactericidal agents. Pluronic-based nanoself-assemblies of bacitracin A (Nano-BAP85) (Hong et al. 2018) and zeolitic imidazolate framework (ZIF) nanodagger arrays (Yuan and Zhang 2017) rescued rats from S. aureus infections and killed 100% of microorganisms inoculated on the surface. Nanostructured polyurethane surface inhibited the growth of Staphylococcus epidermidis, E. coli, and P. mirabilis significantly (Yao et al. 2013) (Table 4).

Methods used in fabrication of nanoparticles

Out of the 22 studies using inorganic NPs, nine studies employed biological means to synthesize and functionalize NPs. Four studies used physical means, while three studies chemically synthesized NPs. However, four studies used NPs purchased from nanotech centers, while two studies did not outline the methods used in fabrication of the NPs (Table 2). All the 15 studies which used inorganic-organic nanopolymers except three employed chemical methods to synthesize the nanocomposites. Two studies used physical methods (UV irradiation to reduce metal ions within the composites into NPs), while in one study, purchased NPs were used to build the nanopolymer (Table 3).

Methods for characterizing nanoparticles

orty-four studies (89.8%) characterized NPs and nanocomposites using different platforms. Platforms used to determine the diameter and size distribution of the NPs included the transmission electron microscopy (TEM), scanning electron microscopy (SEM), field emission transmission electron microscopy (FETEM), and high-resolution transmission electron microscopy (HRTEM). Dynamic light scattering (DLS) was employed to determine the zeta potential and size distribution of NPs. Attenuated total reflectance Fourier transform-infrared (ATR-FTIR) spectroscopy, Fourier transform-infrared spectroscopy (FTIR), and atomic force microscopy (AFM) were applied to analyze the conjugation or capping of nanoparticles with other substances. X-ray diffraction (XRD) and energy dispersive X-ray spectroscopy (EDX) were applied to determine the mineral content, size, and quality of NPs. Differential scanning calorimeter was used to determine the molecular stability of dilute in solution NPs. Thermogravimetric analysis (TGA) was performed to investigate the presence and amount of surface-bound ligand in nanohybrids. UV-visible diffuse reflectance spectroscopy (DRS) was applied to confirm the presence of metal elements; spectroscopic ellipsometry studied the optical properties of nanocomposites. X-ray photoelectron spectroscopy (XPS)/X-ray spectroscopy was used to measure the elemental composition within nanocomposites. UV visible spectroscopy was applied to predict the geometry of nanoparticles and to monitor the process of plant extract-mediated synthesis of NPs (Table 2, 3, and 4).

Characteristics of nanoparticles

Inorganic nanoparticles

Out of the 22 studies which used inorganic NPs, 17 reported the diameter size of NPs synthesized. The size of NPs ranged from 2 to 250 nm in diameter. Gold NPs displayed the smallest diameter (2–5 nm), while silver exhibited the biggest diameter (65–250 nm). Only four studies reported the zeta potential of NPs. Zeta potential varied from − 11.9 to − 31.2 mV. Eight articles reported the shapes of the metal NPs used. The shapes of NPs were spherical, irregular (Naz et al. 2013), triangular, and polygonal (Table 2).

Inorganic-organic nanohybrids

Sixty seven percent (67%) of the studies which investigated the potential of inorganic-organic nanohybrids as drug carriers or antibacterial agents reported the size of the nanocomponents of nanohybrids. The size ranged from 3 to 52 nm. The smallest nanocomponents were CdTe (3-4 nm) harbored in CdTe-TiO2 nanocomposite, while silver-curcumin nanohybrid had the biggest NPs (Zhou et al. 2012). Zeta potential was documented in only three articles. Alves et al. (2017) reported negative zeta potential of − 20 mV in silver-curcumin composite, while positive zeta potentials of + 8.9 mV in pSWCNT-Ag and + 39 mV in MNP-CSA-13 were registered. Only three studies characterized nanohybrids as spherical and conical (Table 3).

Nanoorganic molecules

All the studies which designed nanoorganic materials as nanovehicles for antibacterial agents determined their diameter, while 66.7% (8/12) reported their zeta potential. The diameter ranged from 0.8 to 1 nm in GO-carbon nanotubes to 397 ± 10.1 nm − 7 86.9 ± 11 nm in solid lipid nanodroplets loaded with Eugenia caryophyllata essential oil (SLN-EO). One study determined the diameter of the nanodelivery system before and after loading as 36.7 ± 3.59 nm, − 114.36 ± 55.31 nm, and 267.50 ± 4.99 nm, respectively, in the chitosan nanocarrier-ciprofloxacin complex. Hong et al. (2018) observed that BAP85 nanocomplex with a diameter of 73.3–99.4 nm degraded synthetic bacterial lipopolysaccharide (LPS) from liposome with a diameter of 7000 to 2000 nm. Shaaban et al. (2017) and Yuan and Zhang (2017) reported positive zeta potentials of 17 ± 1.6 mV for imipenem/cilastatin-loaded polycaprolactone (IMP-PCL) nanocapsule; 15 ± 0.6 mV for polylactide-co-glycolide filled with imipenem/cilastatin (IMP-PLGA), and 29 mV for zeolitic imidazolate framework (ZIF) nanodagger arrays, respectively. Six studies documented negative zeta potential with a lower limit of − 43 mV and upper limit of − 3.02 mV. For studies which determined the shape; nanoorganic materials were spherical (Table 4).

Nanomaterial exposure time

Among the studies included in this systematic review, 93.4% (46 out 49) documented the nanomaterial exposure time against bacteria isolates. The exposure time ranged from 0.67 (40 min) to 672 h (28 days) with an average of 48.8 h and model frequency of 24 h (Tables 2, 3, and 4).

Nanoparticle bactericidal mechanisms

Thirteen studies (26.5%) investigated the mechanism of action of NPs. The most common mechanisms included the disruption of the cell membrane leading to the leakage of the intracellular contents, downregulation of proteins, aggregation and melting of bacterial cells, failure of bacterial cells to adhere to the topography (bumps) of nanolayered surfaces, and inhibition of quorum sensing. These mechanisms were revealed through different platforms like, AFM, FESEM, SEM, TEM, EDX, HRTEM, and ART-FTIR in addition to peroxidase assay, superoxide dismutase (SOD) assay, and beta-galactosidase assay (Tables 2, 3, and 4).

Effective nanoparticle concentration/dose

The effective NP formulation concentration ranged from 2 × 10−7 μg/mg (clavanin-methacrylate nanocarrier complex) to 13,900 μg/ml for titanium oxide NPs (Tables 2, 3, and 4). For inorganic NPs, the lowest and highest effective doses were 0.5 μg/ml and 13,900 μg/ml, respectively. The effective concentration for organic NPs varied from 2 × 10−7 μg/mg to 2500 μg/mg, while for hybrid nanocomposites, the effective dose stretched from 7.5 to 10,789 μg/ml. The mean effective dose was highest for inorganic NPs (1361 μg/mg), followed by nanohybrids (905 μg/mg), and organic NPs had the lowest average effective dose of 357.8 μg/mg (Fig. 4). However, statistical analysis did not yield any significant difference in effective doses between inorganic NPs and organic NPs (P = 0.66), inorganic and nanohybrids (P = 0.89), and organic NPs against nanohybrids (P = 0.9). Interestingly, vancomycin alone and mPEG-OA nanocarrier loaded with vancomycin displayed similar efficacies against MSSA and MRSA isolates. However, the effective dose for the former was significantly lower (0.37 μg/mg and 5.86 μg/mg against MSSA and MRSA, respectively) than for the latter (15.62 μg/mg and 31.25 μg/mg against MSSA and MRSA, respectively).

Fig. 4
figure 4

Comparison of mean effective dose between inorganic, hybrid, and organic NPs. Tukey’s multiple comparison test was used to compute and compare the mean effective dose. P values of 0.655 between inorganic NPs and organic NPs, 0.889 for inorganic versus nanohybrids, and 0.895 for organic NPs against nanohybrids were generated, revealing insignificant differences among the effective doses

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Bactericidal efficacy of nanoparticles

Antibacterial efficacy of NPs ranged from 0% for GO nanodelivery system of sulfamethoxazole to 100% in 76.1% of the studies which reported efficacy (Tables 2, 3, and 4). The mode and median efficacy was 100%. Inorganic NPs registered the highest bactericide efficacy of 96.82%, followed by nanohybrid composites at 96.79% and trailed by nanoorganic molecules (83.3%). The overall mean bactericide efficacy of all categories of NPs was 94.7%. Nevertheless, multiple comparisons between inorganic and organic NPs (P = 0.08), inorganic versus nanohybrids (P = 0.9), and organic NP versus nanohybrid (P = 0.1) did not reveal any significant differences (Fig. 5). Furthermore, one study reported 100% and 17% efficacy of gold-copper NPs against Bacillus anthracis cells and Bacillus anthracis spores, respectively. Efficacies of silver NPs against antibiotic-sensitive and MDR P. aeruginosa biofilms were 67% and 56%, respectively. Five studies investigated the efficacy of NPs against bacterial biofilms (Tables 2 and 3). The NP antibacterial efficacy ranged from 50 to 100% with a mean value of 71.97%. Single-factor ANOVA revealed that NP efficacy against bacterial planktons and biofilms was significantly different (P < 0.002). It is worth noting that Jafari et al. (2017) observed a synergism between silver-zinc oxide NPs and rifampicin with efficacy of 100% against rifampicin-resistant H37RV Mtb phagocytized by THR1 cell lines, while the latter and former individually exhibited 0% efficacy.

Fig. 5
figure 5

Comparison of mean percentage efficacies between inorganic, hybrid, and organic NPs. Tukey’s multiple comparison test was used to calculate and compare the mean percentage efficacies giving P values of 0.0833 for inorganic versus organic NPs, > 0.9999 for inorganic versus nanohybrids, and 0.1080 for organic NP versus nanohybrid, revealing considerable similarities

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Nanoparticle toxicity

Nanoparticle biocompatibility studies were carried out in 14.3% of the studies. Ex vivo cytotoxicity assay of silver NPs, silver zinc oxide NPs, mPEG, PHEMA hydrogel, and Nag-PLGA were performed against human dermal fibroblasts (Reithofer et al. 2014), human macrophage cell line (THP-1) (Jafari et al. 2017), human breast adenocarcinoma (MCF7); adenocarcinoma human alveolar basal epithelial cells (A 539), human liver hepatocellular carcinoma (HepG 2) (Omolo et al. 2017), NIH-3 T3 fibroblasts (Xu et al. 2018), and preosteoblastic MC3T3-E1 cell line (Zhenga et al. 2010), respectively, using the MTT cell proliferation assay. Ex vivo cytotoxicity investigation of TPU-DA nanosilver complex was tested on HaCaT cells and NIH 3T3 fibroblasts using the CCK8 assay (Liu et al. 2018). In vivo toxicity of pSWCNT-Ag was done using chick embryos (Park et al. 2018). Results from all the biocompatibility assays exhibited that the nanomaterials were not toxic as cell viability of above 75% in the presence of nanotherapeutic agents was registered.

Discussion

Fabrication of organic nanoparticles

Synthesis of inorganic nanoparticles using traditional approaches such as chemical and physical methods has shortcomings. Physical approaches are not cost-friendly as they require exceedingly expensive equipment which use high energy, temperature, and pressure (Guzmán et al. 2009). Chemo-nanoparticle fabrication mainly entails wet chemistry where numerous reducing agents are employed to reduce metal salts to their nanoform in solutions (Tahir et al. 2013). The use of hazardous solvents and reducing agents during chemosynthesis results into contaminated NPs that are toxic to both target bacterial and host cells (Kawata et al. 2009). Moreover, several stabilizers are also required to prevent agglomeration of nanoparticles when in solution to functionalize and enhance their biocompatibility (Castro et al. 2014). To combat these drawbacks, novel, inexpensive, unsophisticated, and environmentally friendly biological approaches such as green synthesis of nanoparticles using plant extracts have been explored (Huang et al. 2014). Plant extracts with antioxidant properties have gained immense attention owing to their ability to scavenge electrons from metal ions, thereby reducing them to their nanoscale as well as functionalizing them (Khan et al. 2013). This is in agreement with the majority of the studies which used inorganic nanoparticles included in this review. Among the 16 studies which synthesized in-house inorganic NPs, 56.3%, 25%, and 18.8% used biological, physical, and chemical methods, respectively. This clearly shows an inclination toward biosynthesis of inorganic NPs from their metal ions. Furthermore, biological approaches are becoming more popular in resources, facilities, and technical limited environments as they are cheap and eco-friendly and they yield functionalized non-toxic NPs.

Physicochemical properties of nanoparticles

The antibacterial activity of NPs depends on their physicochemical characteristics such as size, shape, and zeta potential. Minute NPs have very high chemical reactivity and bacterial cell wall and membrane penetrative power as compared with their bigger counterparts, hence potent bactericide effect on bacterial cells at very low minimum inhibitory concentration (MIC). Lu et al. (2013) reported silver NPs with a diameter of 5 nm exhibited the highest antimicrobial activity with a MIC value of 25 μg/ml. Furthermore, bactericidal action of the NPs is reliant on both size and shape; hence, variability in the mode of action of different forms of NPs may enlighten why resistance to this treatment is yet to be reported (Kvitek et al. 2008; Markova et al. 2012). Therefore, knowing the size and shape distribution of the NPs elucidates their efficacy. Zeta potential is an important aspect in the application of NPs as antimicrobial agents. Nanoparticles with a negative zeta potential tend to agglomerate to form bigger clusters when in solution, hence compromising their advantage over non-nanoforms, and they are repelled by a negative charge possessed by the bacterial cell membrane. On the other hand, NPs with a positive zeta potential singly remain in solution, and their positive charge is highly attracted to the negative charge of the bacterial cell membrane, thereby enhancing their adsorption to the bacterial cells. Therefore, zeta potential is a fundamental factor for the stability of nanoparticles in solution. A zeta potential of at least ± 30 is required for minimum NPs’ stability (Muller et al. 2001). Fortunately, 89.9% of the studies included in this review characterized the NPs to determine their physicochemical characteristics using TEM, HRTEM, SEM FESEM, and DLS.

Drug nanodelivery systems

Peptides, lipids, antibodies, and cytokines have exhibited potent antimicrobial activity, but properties such as low solubility, short half-life, and bio-incompatibility in the circulatory system have hindered their pharmaceutical applicability (Pini et al. 2005). Nanoencapsulation as drug delivery systems augment therapeutic efficiency of these molecules by increasing their bioavailability and penetration across biological membranes. Furthermore, nanodelivery systems sustain controlled drug release, hence maintaining the required plasma drug concentration. Drug nanocarriers afford drugs a mechanism of evading the pathogens’ molecular resistance mechanisms such as gained antibiotic resistance through alteration of the surface membrane proteins and protection against hydrolytic enzymes which degrade antibiotics (Devalapally et al. 2007; Sadurní et al. 2005). This is in agreement with the studies included in this systematic review which used nanobiotechnology to design drug delivery systems. Li et al. (2010, 2009) designed monocyte chemoattractant protein-1(MCP-1) and interleukin-12 p70 (IL-12p70) nanocoatings on orthopedic implants and multilayer polypeptide nanoscale coatings incorporating IL-12. These drug nanocarriers maintained the bioavailability and release of pro-inflammatory molecules. This technology provoked the cell-mediated immunity in open fractures of rat models, hence enhancing the immune-mediated cytotoxicity against MRD and sensitive S. aureus infections. Bismuth NPs conjugated with polyclonal P. aeruginosa antibodies enhanced their antibacterial activity against MDR P. aeruginosa with an efficacy of 90% as compared with 6% for the antibodies alone (Luo et al. 2013). Nanoencapsulation of clavanin A peptide with methacrylate (Saude et al. 2014), C. flexuosus oil with nanoemulsion (Da Silva Gündel et al. 2018), and E. caryophyllata essential oils with solid lipid NPs (Fazly Bazzaz et al. 2018) enhanced their antibacterial efficacy to 100% in in vivo and in vitro systems compared with the controls. Enhanced antibacterial activity of nanoencapsulated molecules may be attributed to their increased bioavailability as the nanocapsules protect them from the destabilizing factors of the external environment.

Chitosan loaded with ciprofloxacin (Marei et al. 2018), mPEG-OA nanocarrier encapsulating vancomycin (Omolo et al. 2017), and nanoencapsulation of imipenem/cilastatin by polycaprolactone (PCL) and polylactide-co-glycolide (Shaaban et al. 2017) boosted the bactericidal effect of the antibiotics on sensitive and MDR bacteria. The high efficacy of antibiotics delivered by nanocapsules is attributed to the capability of nanocapsules to protect the drugs from the hydrolytic enzymes secreted by resistant bacteria. Moreover, encapsulated drugs such as carbapenems disguisedly diffuse across the cell membrane of resistant bacteria with mutant porins. Contrary to that, GO nanodelivery system of sulfamethoxazole (SMZ) considerably subdued the intracellular abundance of SMZ. GO augmented the diffusion of SMZ from the intracellular to the extracellular environment by increasing the cell membrane permeability. In addition, GO-SMZ complex reduced the uptake of SMZ into the bacteria (Zou et al. 2016).

Furthermore, to design a competent drug nanodelivery system, one needs to understand the mechanism of interaction between the nanovector and the drug, the conditions under which the drug will dissociate from the nanocarrier and hence its release and the combinatory effect of the nanocarrier and the drug. If there is no possible bondage, a linker between the nanocarrier and the drug or material to be delivered is a possible option. Among the articles included in this systematic review, two articles reported the application of a linker to form nanocarrier drug/material complex: Chatterjee et al. (2011) created an interaction between gold NPs and plasmid DNA using glutathione as a linker. Glutathione interacts electrostatically with both DNA and gold nanoparticle. The association with DNA is through free-end g-glutamine residue amine group which non-specifically interrelates with the negatively charged phosphate group of DNA, while the carboxyl group of glycine residue electrostatically interacts with the positively charged gold nanoparticle to form glutathione-functionalized gold nanoparticle. Therefore, the electrostatic interaction of gold NPs, glutathione, and DNA results into a reversible electrostatic gold-glutathione-DNA complex which releases DNA once inside the cell due to ionic variation. Hence gold-glutathione-plasmid DNA (with ampicillin-resistant gene) complex was designed and used to deliver ampicillin-resistant gene to E. coli. It is worth noting that gold NPs exhibited no growth inhibitory effect against E. coli at a very high concentration of 100 μg/ml there non-toxic but demonstrated potent material delivery activity hence a candidate for drug delivery.

In another study, Niemirowicz et al. (2015) fabricated a ceragenin-coated iron oxide magnetic NPs (MNP-CSA-13) hybrid. Despite the potent antimicrobial activity of ceragenin (CSA-13), a synthetic peptide, safety concerns due to its non-selective toxicity have limited its use (Lai et al. 2008). However, MNP-CSA-13 nanocomposite formed from the conjugation of iron oxide magnetic NPs (MNP) with CSA-13 targeted only P. aeruginosa biofilms and free-living cells at very high concentration of 100 μg/ml. No hemolysis of erythrocytes was observed showing that conjugation of synthetic peptides with nanocarriers minimizes host cytotoxicity (Zhao et al. 2009). The link between MNPs and CSA-13 was established through glutaraldehyde (Massart 1981). The treatment of MNPs with 3-aminopropyl trimethoxysilane (APTMS) results into a functional amino-terminated silica on the MNPs surface which reacts with glutaraldehyde. The terminal aldehyde groups on the MNP surface forms a platform for binding of CSA-13 where they react with the primary amine groups of CSA-13. MNP-CSA-13 might dissociate under low pH due to infection and inflammation. This potentiates the MNP-CSA-13 nanocomplex to dissociate and release CSA-13 antimicrobial peptide due to the hydrolysis of the imine bond at low pH. Therefore, MNP-CSA-13 is a promising nanodrug vector for pH-dependent conventional antimicrobial delivery/release to kill pathogens at infection sites where the pH is often lower than six (Kierys 2014).

Nanoparticle bactericidal mechanism of action

To date, the bactericidal mechanism of NPs is yet to be fully clarified. However, for inorganic NPs, it might reside within the capacity to discharge cations which irreversibly perforate bacterial cell wall, inactivate vital proteins, and chelate DNA or through generation of reactive oxygen species (ROS) (Slavin et al. 2017; Rizzello and Pompa 2014). Disintegration of the bacterial cell wall and membrane inhibition of protein synthesis were confirmed by some studies included in this review (Sowmya et al. 2018; Seil and Webster 2012; Ansari et al. 2014; He et al. 2016; Khan et al. 2016; Addae et al. 2014; Park et al. 2018; Su et al. 2011; Niemirowicz et al. 2015; Zanni et al. 2017; Gholap et al. 2013; Hong et al. 2018). In these studies, AFM, FESEM, SEM, TEM, EDX, HRTEM, and ART-FTIR revealed that disintegration of the cell membrane was through puncturing action of NPs which is contrary to cations mediated degeneration of the cell membrane. Though two studies (Seil and Webster 2012; Khan et al. 2016) reported cell membrane collapse through liberation of ROS that seems to be arbitrated by the discharge of cations, this clearly explains why NPs and nanomaterials are the most promising candidates to supplement or be co-administered with antibiotics. When NPs inactivate vital proteins, chelate DNA, and inhibit protein synthesis, bacterial cells become incapacitated to launch any molecular mechanism of antibiotic resistance as such mechanisms totally depend on the metabolic pathways and cellular structures affected by the nanomaterials.

Shift from ultraviolet to visible light responsiveness

Traditionally, the antibacterial activity of titanium lies in its activation by ultraviolet (UV) light illumination. This limits the application of titanium-based compounds as antibacterial agents in vivo since the catalyst UV light is invasive to mammalian cells. Therefore, its applicability as a bactericidal agent is restricted to abiotic environments. However, titanium in nanoscale form can be modified to shift from low wavelength absorption spectrum to higher wavelength as revealed by three studies included in this review. Gholap et al. (2013) conjugated TiO2 NPs to CdTe QDs, Senarathna et al. (2017) capped TiO2 NPs with Garcinia zeylanica extract, and Cheng et al. (2009) coated nanostructured TiO2 powder with carbon. These surface modifications of TiO2 NPs transferred the bactericide activity of TiO2 photocatalyst from UV light to visible light responsive. Therefore, the induced ability of TiO2 in its nanoform through surface manipulation to absorb light from the visible spectrum highlights its possible applicability as an antimicrobial agent in biotic environments.

Nanoparticle bactericidal efficacy versus dose

The bactericidal efficacy of a number of antimicrobial agents is dose dependent (McKenzie 2011; Levison and Levison 2009). However, high concentrations exhibit non-selective cytotoxicity. Therefore, therapeutic agents with very low minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) are preferred. Nanoscale molecules present very high chemical reactivity, solubility, and hence more efficacious bacteria inhibitory effect at very low concentrations as compared with their non-nanoscale forms (Slavin et al. 2017). These attributes made them the preferred future antimicrobials and antimicrobial carriers. Intensive research is being carried out to develop and assess nanomolecules as possible antibacterial alternatives and potentiators of bactericidal agents as carriers. Contrary to this, most studies incorporated in this review observed that nanomolecule bacterial growth inhibitory efficacy is dose dependent with mean effective concentrations of 357.8 μg/mg, 905 μg/mg, and 1361 μg/mg for organic NPs, nanohybrids, and inorganic NPs, respectively. These means are way above the recommended NP non-toxic dose (100 μg/mg) to mammalian cells. Surprisingly, Jafari et al. (2017) and Reithofer et al. (2014) reported that Ag NPs and AGZnO nanocrystals were non-toxic to mammalian cell lines at very high concentrations of 1078.9 and 512–8192 μg/mg in ex vivo experiments. Articles included in this review presented undisputable potent NP antibacterial efficacy against antibiotic-resistant and sensitive clinical isolates as revealed by the mean (94.7%), median (100%), and mode (100%) efficacies of in vitro and in vivo therapy. For safety concerns, the stumbling block lies in the formulation of nanotherapeutic agents with efficacious biocompatible doses in in vivo systems.

Efficacy of nanoparticles against bacterial biofilms and spores

Bacterial biofilms are known to be exceedingly tolerant and resistant to antibiotics as they provide optimal environments for transfer of plasmids harboring antibiotic resistance genes via conjugation as well as the biofilm matrix protecting bacteria cells in lower films against antibiotics (Lowy 2003; Warnes et al. 2012; Ceri et al. 1999). Inorganic and organic nano-ordered surfaces and coatings are presently topping the options for medical device surface modification to prevent biofilm formation (Rizzello and Pompa 2014; Taylor and Webster 2011; Nair and Laurencin 2008). This conclusion is in agreement with the investigations of Yao et al. (2013) and Yuan and Zhang (2017) where zeolitic imidazolate framework (ZIF), nanodagger arrays, and nanostructured polyurethane significantly prevented the formation of Staphylococcus epidermidis, E. coli, P. mirabilis, and S. aureus biofilms perhaps by the failure of bacterial cell to conform to the topography of the nanolayered surface. Conversely, NP formulations aimed at eradicating already formed biofilms yielded unpromising results comparable with antibiotics with bactericide efficacies as low as 50% and mean efficacy of 71.97%. Additionally, gold-copper sulfide NPs were ineffective against Bacillus anthracis spores at very high concentration (1081 μg/ml) (Addae et al. 2014). This is analogous with conclusions from other studies which used antibiotics (Louie et al. 2012).

Nanomaterial exposure time against bacteria

One of the factors influencing the evolution of antimicrobial resistance is the exposure time of antimicrobial agents against pathogens. Graves et al. (2015) observed that the consequential resistance to Ag NPs in E. coli was acquired by the 200th generation equivalent to over 10 days of exposure. However, the mode and average exposure times in articles included in this systematic review were 24 h and 48.8 h corresponding to approximately 6.5 and 13 generations, respectively. This might be the reason why high nanomaterial bactericidal efficacies were attained against clinical isolates in in vitro and in vivo experiments.

Biocompatibility studies

For safety reasons, it is a prerequisite to assess the toxicity level of any novel potential therapeutic agents using mammalian cells (Choksakulnimitr et al. 1995). This can be achieved by exposing the cells to the new therapeutic agent and cell viability computed using cytotoxicity calorimetric assays such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT), and Cell Counting Kit-8 (CCK8). MTT, XXT, and CCK8 are tetrazolium yellow dyes. The principle behind these calorimetric assays lies in the ability of viable cells to reduce the yellow tetrazolium salt to formazan, an insoluble deep purple crystalline product. The intensity of the deep purple color formed in cells is directly proportional to the number of viable cells and can be assayed calorimetrically. This is because the activity of NADH-/NADPH-dependent oxidoreductase enzymes that reduce the MTT, XTT, and CCK8 dyes is maintained. To complement ex vivo experiments, in vivo cytotoxicity assays can be carried out by injecting nanoparticle formulations into embryos of model organisms followed by assessing their survival. This is in agreement with only 14.3% of the studies included in this systematic review. These studies reported cell viability of above 75% in the presence of nanotherapeutic agents comparable with the controls. Cell viabilities of 75% are considered to be biocompatible to mammalian cells (Hamid et al. 2004; Mosmann 1983). The similar reduction of cell viability of up to 25% in mammalian cell lines treated with nanoparticles and controls can therefore be attributed to alteration in local cellular microenvironment. However, Jafari et al. (2017) and Liu et al. (2018) observed that cell viability decreased with increasing concentration of nanoparticles administered. This is an indicator that high nanoparticle concentration compromises biocompatibility. Therefore, as a biosafety measure, NP formulations require very minute concentration but with potent antibacterial activity.

Conclusion

Due to the ever-increasing prevalence of antimicrobial resistance to old and newly synthesized drugs, alternative antimicrobials to replace or supplement available drugs are needed. The importance of nanotechnology in developing alternative antibacterial agents and antimicrobial enhancers such as nanocarriers has been confirmed in both in vitro and in vivo models. Studies assessed in this review revealed high bactericidal efficacies of organic, inorganic, and hybrid NPs. Notable example is where imipenem nanocarrier augmented its antibacterial effect against carbapenem-resistant clinical isolates. However, bactericidal efficacy of NPs is dose dependent necessitating the use of high concentration of NPs way above the MIC to achieve potent treatment outcomes albeit with non-selective toxicity. Therefore, there is still a limitation of formulating effective concentration of antibacterial nanotherapeutic agents that are biocompatible in in vivo systems. Furthermore, ROS generated by bacterial cells may not only disintegrate the bacterial cell membrane but also rapture the host cell membrane. As a safety precaution, in vitro, ex vivo, and in vivo cytotoxicity assays should be conducted to guarantee the safety of patients.