Introduction

Enteric fever, also known as typhoid fever, primarily attributed to Salmonella enterica and Salmonella typhimurium species is recognized as a potentially serious foodborne illness across the globe (Almuzaini 2023). Salmonella enterica infection can lead to a variety of symptoms, from minor gastroenteritis to severe systemic ailments, and can have life-threatening consequences (Borges et al. 2013). As per Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017, it is estimated that 93.8 million people suffered by Salmonella infections and approximately 1.55 Lac deaths incurred every year worldwide (Balasubramanian et al. 2019). The ever-increasing incidence rate of foodborne diseases in developing nations is a profoundly concerning problem that requires immediate contemplation (Mandal et al. 2014). In Indian context, the incidence and mortality rates associated to enteric fever are increasing significantly every year, with a mortality rate ranging from 10 to 30%. According to National Incidence of Enteric Fever database indicates that approximately 4.5 million individuals are afflicted by enteric fever annually, resulting in an estimated 8930 deaths (Kumar et al. 2022). Such alarming situation imposes the critical need for immediate and focused attention to address this persistent communal health concern.

To combat the Salmonella enterica infections, first-line choice antibiotics included ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole. The upsurge in Salmonella infection has accorded an uptick in uncontrolled antibiotic administration which led to the emergence of resistance to antimicrobial treatments in Salmonella enterica (Khameneh et al. 2019; Elmongy et al. 2022). Rapid emergence of multi-drug resistant (MDR) strains of S. enterica led to the utilization of fluoroquinolones class of antibiotics, viz., ofloxacin, levofloxacin, and ciprofloxacin (Browne et al. 2020). With the recent advent of fluoroquinolone-resistant Salmonella strains, third generation cephalosporin and azithromycin are the recommended choice of antibiotics to combat Salmonella enterica infections nowadays (Nair et al. 2018). Owing to the upsurge of MDR/XDR strains of Salmonella enterica and the significant peril it poses to public health, the World Health Organization (WHO) has prioritized the advancement of innovative antibiotics with much wider spectrum of activity (Elmongy et al. 2022).

Since many decades, medicinal plants are well known for their therapeutic properties and being employed as herbal remedies in the management of a wide array of infectious diseases. Out of about 17,000 higher class Indian plants, 7500 plants exhibit medicinal attributes towards various lifestyle and infectious disorders (Ashraf et al. 2023). Medicinal plants are reported to be reservoir of plethora of bioactive phytochemicals with diverse structural and functional attributes and have been an integral component of traditional medicines. Protuberant examples of bioactive compounds harnessed from medicinal plants encompass alkaloids, terpenoids, coumarins, flavonoids, nitrogen-containing compounds, organosulfur compounds, and phenolics (Al-Abd et al. 2015), which are being employed against various drug-resistant bacterial strains like Escherichia coli, Salmonella typhimurium, Salmonella enterica, Pseudomonas aeruginosa, Klebsiella pneumonia, and Staphylococcus aureus. Much of the evidence validates the significant contribution of phytochemicals obtained from the extracts of medicinal plants (Wang et al. 2020) as valuable source of anti-cancer, antioxidant, antidiabetic, immunosuppressive, antifungal, anti-inflammatory, antimalarial, antibacterial, anti-fever, and antiviral agents (Borges et al. 2016). Therefore, continual efforts are being put forth by researchers to discover new phytochemicals obtained from medicinal plants, so that new and better drugs can be developed to cater the recurrent and frequent episodes of infections from multi-drug resistant strains of Salmonella enterica (Mehta et al. 2016).

Emergence of antibiotic resistance

Salmonellosis is considered to be the most common infectious disease among range of foodborne illness diseases worldwide. The extensive utilization of range of antimicrobial compounds in typhoid and paratyphoid has led to the development of resistant strains of Salmonella, thereby limiting treatment options and increasing the prevalence of Salmonella infection. The evolution of MDR strains of Salmonella began in the 1980s (Eng et al. 2015) due to multiple acquisitions of plasmids. Compared to previous years, the MDR strains of S. enterica were 0.41% in 2005, which increased to 1.71% in 2019 (Pietsch et al. 2021). Centers for Disease Control and Prevention (CDC) detected antimicrobial resistance to various antibiotics such as ampicillin, chloramphenicol, streptomycin, tetracycline, fluoroquinolone, third-generation cephalosporin, and trimethoprim-sulfamethoxazole, used against Salmonella sp. infection by detecting the existence of resistance genes by employing polymerase chain reaction (PCR) (Pinto et al. 2010). The Salmonella enterica and Salmonella Typhi clinical strains conferring resistance to chloramphenicol, ampicillin, and trimethoprim–sulfamethoxazole were categorized as multi-drug resistant (MDR) strains. However, the isolates that were recognized as MDR and also displayed resistance towards fluoroquinolone-based antibiotics and third-generation cephalosporins were classified as extensively drug resistant (XDR). The major genes accountable for conversing resistance towards third-generation class of antibiotics, viz., cephalosporins, were found to be linked with the presence of AmpC β-lactamase genes such as blaCMY-2 (Lynee et al. 2008), blaACC-1, and extended-spectrum β-lactamase (ESBL) gene blaSHV-12, while azithromycin resistance was related with the existence of acrB gene (Table 1).

Table 1 Antibiotic resistance gene (s) with primer pair, size reported in Salmonella species
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In 2017, the World Health Organization described fluoroquinolone-resistant S. enterica as a form of plasmid-mediated quinolone resistance (PMQR) (Chang et al. 2021) indicating low levels of quinolone susceptibility with mutations in DNA gyrase (topoisomerase II) and topoisomerase IV in Salmonella. It results from a double mutation in gyrA gene and a single mutation in parC gene. The resistance to ciprofloxacin in Salmonella is determined by genes, viz., qnrA, qnrB, qnrC, qnrD, qnrS, aac(6')lb-cr, and oqxAB (Jiang et al 2014; Lin et al. 2015). Clinical and Laboratory Standards Institute (CLSI) report in 2015 showed that azithromycin resistance in Salmonella enterica was due to mutations in acrR, rplD, and rplV genes (Sajib et al. 2021). In third-generation cephalosporins, the main cause of Salmonella-resistant strains was the production of extended spectrum beta lactamase (blaCTX-M-1, blaCTX-M-14, and blaCTX-M-65) or AmpC beta lactamase (Pietsch et al. 2021).

Phytochemicals as a remedial approach

Since antiquity, medicinal plants have been utilized as sources of traditional medicine in Unani Hakim and Indian Vaids (Sen & Chakraborty 2016). Plants have been an indispensable source in providing food additives and industrial biochemicals and aiding in the treatment of infectious ailments as well as contributing significantly in meeting the daily life needs. As per report of WHO, approximately 80% of the drugs offered for the management of range of infectious and life style diseases are derived from plants being less immunogenic, more efficient, and of lower cost also (Sharma and Alam 2022). Bioactive organic substances found in plants are synthesized from the primary or secondary metabolism of living organisms, which are chemically and taxonomically diverse (Yadav and Agarwala 2011). Among these substances, tannins, alkaloids, flavonoids, phenolic, carbohydrates, steroids, glycosides, and saponins are prominent, whose are obtained from various parts of medicinal plants like bark, leaves, stem, roots, flowers, fruits, and seeds. They are used in human medicine, veterinary medicine, scientific research, and many other fields (Anand et al. 2022). Terpenoids and tannins are used in analgesic and anti-inflammatory activities; saponins are used in the treatment of fungal, bacterial, and yeast infections; flavonoids are used in the treatment of allergy, inflammation, platelet aggregation, pathogens, ulcers, hepatoxins, viruses, and tumors; and cardiac glycosides are used in treatment of heart failure (Yadav and Agarwala 2011). Many plant-derived bioactives have shown potential as antipyretic, diuretic, analgesic, anthelmintic, antiseptic, antitumor, and anti-inflammatory agents (Table 2).

Table 2 Medicinal plants and their parts with therapeutic potential
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Many studies reported the whole plant as well as different plant parts, viz., shoot, root, seed, leaves, bark, flowers, and inflorescence of various medicinal plants belonging to Fabaceae, Simaroubaceae, Scrophulariaceae, and Lythraceae family possess bioactive compounds to be exploited against treatment of fever, cough, cold, malaria, piles, etc. (Arya et al. 2022). Phenolic compounds extracted from leaf of Justicia zeylanica and leaf, bark, and pods of Acacia nilotica were observed to exhibit antimicrobial activity towards S. aureus and E. coli. However, J. zeylanica was also active against B. cereus, L. monocytogenes, S. typhimurium, Y. enterocolitica, V. cholera, and S. flexneri (Aggarwal et al. 2022). Further, bioactive compounds harnessed from Acacia nilotica exhibited antimicrobial potential against M. tuberculosis, P. aeruginosa, and S. enterica (Sadiq et al. 2015). Numerous previous studies have documented the role of novel phytochemicals with great antimicrobial spectrum against range of infectious micro-organisms, viz., Pseudomonas aeruginosa, P. falciparum, B. subtilis, S. aureus, S. Typhi, C. albicans, Aspergillus niger, P. vulgaris, S. pyogenes, and K. aerogenes, thereby validating the immense chemical diversity with bioactive/therapeutic potential of medicinal plants (Table 3).

Table 3 Antibacterial potential of various classes/phytochemicals harnessed from different parts of medicinal plants
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Anti-salmonella potential of phytochemicals

In catering Salmonella enterica infection, many novel bioactive compounds have been harnessed from medicinal plants with much increased efficacy and potency. Ethanolic and aqueous extracts of Khaya senegalensis exhibited promising anti-salmonella activity at different concentrations ranging from 50 to 500 mg/mL with zone of inhibition ranging from 14 to 27 mm (Ugoh et al. 2014). A previous study detailing the in vivo anti-salmonella activity of aqueous extract of Euphorbia prostrata also reported the considerable decline in viable no. of Salmonella typhimurium recovered from the feces after 8–10 days (Tala et al. 2015). Aqueous extracts of the leaf, stem, and root of Abrus precatorius inhabiting Kwara State, Nigeria, were reported to produce mixture of phytochemicals comprising different concentrations of tannin, saponins, alkaloids, flavonoids, terpenoids, steroids, and phenols in all plant parts with antibacterial activity against S. Typhi with MIC of 40 mg/mL (Sunday et al. 2016). There exist many reports documenting the antibacterial action of essential oil purified from various medicinal plants (Oussalah et al. 2007). Miladi et al. (2016) observed anti-salmonella activity of essential oils of three Mediterranean plants, viz., Satureja montana L, Thymus vulgaris L., and Rosmarinus officinalis L., belonging to Lamiaceae family. The study revealed that S. montana L. and T. vulgaris L. essential oils possess remarkable anti-biofilm, anti-adhesive, and bactericidal properties. Furthermore, essential oil and its synergistic effect along with antibiotics were also reported in multiple scientific studies. Essential oil and methanolic extracts of Nigella sativa exhibited potent antibacterial action towards resistant strains of S. enterica with MIC value ≥ 1000.0 ± 322.7 μg/mL and ≥ 562.5 ± 384.1 μg/mL, respectively (Ashraf et al. 2018). A study documenting the bactericidal potential of ethanolic extract of Punica granatum L. (different parts—peels, seeds, juice, and flowers) against Salmonella enterica serovars Kentucky and Enteritidis isolated from chicken meat was carried out. The findings revealed that the most compelling antibacterial effect against Salmonella strains was exerted by the ethanolic extract of peels, demonstrating MIC values between 10.75 and 12.5 mg/mL (Wafa et al. 2017). Mahlangu and coworkers (2017) reported the potent anti-salmonella activity of dichloromethane, methanol, and acetone leaf extracts of an African medicinally important plant, viz., Albizia gummifera against Salmonella typhimurium, S. Enteritidis, S. Dublin, and S. gallinarum, with MIC and MBC values ranging between 0.125–1 mg/mL and 0.25 to > 2.00 mg/mL, respectively. In last decade, multiple studies documenting the antibacterial potential of different solvent extracts from medicinal plants, viz., ethyl acetate extract of Streblus asper against S. paratyphi (zone of inhibition, 38 mm) with MIC value of 12.50 mg/mL (Arulmozhi et al. 2018) and methanolic, ethyl acetate extracts of North-Western Himalaya medicinal plants (Pistacia integerrima, Ocimum sanctum, Centella asiatica, Momordica charantia, Zingiber officinale, and Withania somnifera) in combination with ciprofloxacin and tetracycline, exhibited promising synergistic antimicrobial activity with GIIs of 0.61–1.32 and GIIs of 0.56–1.35, respectively (Mehta et al. 2022).

The study carried out by Mbock et al. (2020) demonstrated that the hydroethanolic extract of Detarium microcarpum root bark as well as the purified compound rhinocerotinoic acid exhibited promising anti-salmonella activity in infected animals with an effective dose (ED50) of 75 mg/kg. Besides conventional screening and evaluation methods, GC–MS analysis coupled with molecular docking and ADMET profiling of methanolic extract of Psidium guajava displayed that the four compounds, namely, (4-[5-(4-pyridinyl)-1,2,4-oxadiazol-3-yl]-1,2,5-Oxadiazol-3-amine; Cholesta-3,5-diene; 2-hydroxy-Cyclopentadecanone; Oxane-2,4-dione, 6-(4-methoxypheny l)-3,3,5,5-tetramethyl-), exhibited better binding affinity ranging between − 6.6 and − 7.4 kcal/mol with DNA gyrase subunit A of S. typhi as compared to standard drug ciprofloxacin (− 6.4 kcal/mol) (Adetutu et al. 2021). Another investigation focused on screening extracts of Adhatoda vasica, Amaranthus hybridus, and Aloe barbadensis (including leaf, seed, root, and stem) reported that the seed extract of Amaranthus hybridus in hexane exerted the higher antibacterial potential of 93.7% by against S. enterica serovar typhi at 1.25 mg/mL concentration. Moreover, the leaf extract of Aloe barbadensis and chloroform leaf extract of Adhatoda vasica exhibited 92.3% and 80.5% anti-salmonella potential at 10 mg/mL and 40 mg/mL concentration, respectively (Naz et al. 2022).

More recently, ethanolic extracts of 24 plants from Benin folk medicine system were screened for their in vitro and in vivo anti-salmonella activity against clinical resistant strain of Salmonella enterica serovar typhimurium. Out of 24 plants, 18 plant extracts were reported to exhibit the promising anti-salmonella potential with maximum activity observed in Anacardium occidentale, Artemisia afra, Detarium microcarpum, Detarium senegalense, and Leucaena leucocephala against Salmonella enterica strains with minimum inhibitory concentrations (MICs) ranging from 0.156 to 1.25 mg/mL (Amoussa et al. 2023). A much recent study documenting the potential of ethanolic extracts of Hibiscus sabdariffa and Aspilia africana was found to exhibit both bactericidal and bacteriostatic activities against resistant S. Typhi and sensitive S. Typhi with MIC value of 3.125–6.125 mg/mL and 12.5–25 mg/mL, respectively. Further, a synergistic study of ethanol extracts of H. sabdariffa, A. africana, and ciprofloxacin indicated effective MBC value of 0.19–0.39 mg/mL to 0.097–0.19 mg/mL against both the sensitive and resistant strains of S. Typhi, respectively (Balali et al. 2023). Apart from exploring the various solvent extracts of medicinal plants for anti-salmonella potential, multiple compounds have been purified from medicinal plants inhabiting diverse habitats with remarkable activity against Salmonella species (Table 4 and Fig. 1).

Table 4 Anti-salmonella potential of purified compound from medicinal plants, Mechanism of action and MIC value
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Fig. 1
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Structures of major plant-derived compounds for potent anti-salmonella activity

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Herbal formulations from clinical trials to commercialization against Salmonella sp.

Numerous medicinal plants with broad spectrum antimicrobial potential have gained importance in recent years to be developed as herbal medicines as an alternative to conventional antibiotics for catering the infections caused by multi-drug resistant microbes (Khameneh et al. 2021). The herbal medicines/formulations are usually mixture of two or more complex bioactive constituents derived from various ethnobotanical plants while ensuring dosage, efficacy, and safety. Few of such herbal formulations native to certain regions across the globe are well adopted by local people for combating the infections caused by Salmonella species.

MA 001

Since last two decades, an aqueous herbal decoction, namely, MA 001, manufactured by the Centre for Plant Medicine Research (CPMR), Mampong-Akuapem, has been deployed for the treatment of typhoid fever among local communities in Ghana. It is registered with the Food and Drugs Authority of Ghana under the brand name MA 001 (FDA/HD.07–7097). MA 001 is formulated from various plant parts, viz., leaves and aerial parts of Citrus aurantifolia, Spondias mombin, Lantana camara, Bidens pilosa, Trema occidentalis, Psidium guajava, Morinda lucida, Vernonia amygdalina, Persea americana, Paullinia pinnata, Momordica charantia, and Cnestis ferruginea. With a pre-requite to improve the stability, taste, and palatability along with strict compliance, the MA 001 formulation has also been developed in the form of capsules as well as effervescent granules (Kumadoh et al. 2015; Adi-Dako et al. 2021). For the treatment of typhoid fever, dosage regimen of 30 mL of MA 001 three times daily for 3 weeks was fixed. The batch-to-batch consistency analysis of MA 001 formulation based upon organoleptic, physicochemical parameters, pharmacological, and safety was found to pass all the quality standards thereby ensuring reproducibility, efficacy, and safety of MA 001 decoction (Adi-Dako et al. 2023).

Scutellaria baicalensis Georgi (SBG)

It is considered to be golden medicinal herb in Japanese and Chinese pharmacopeia due to the presence of active compound baicalein (Zhao et al. 2016). Traditionally, SBG is being deployed for the treatment of inflammatory and range of infectious disorders including pathopyretic sores, ulcers, or pustules (Xing et al. 2017). The SBG was found to exert antibacterial action towards a wide range of pathogenic bacteria such as Staphylococcus aureus, S. mutans, E. coli, P. aeruginosa, Salmonella enterica, S. epidermidis, and Propionibacterium acnes (Zhao et al. 2019). Multiple studies demonstrated the effect of SBG alone or in combination with potent antibiotics to control the infectious diseases by blocking CTX-M-1 mRNA expression (Cai et al. 2016), increasing cytoplasmic membrane permeability (Siriwong et al. 2015), and inhibiting the NorA efflux pump activity and pyruvate kinase enzyme (Chan et al. 2011).

Houttuynia cordata Thunb (HCT)

In the Chinese pharmacopeia, fresh/dried aerial portion of Houttuynia cordata Thunb. (HC) is being administered to treat various diseased conditions such as purulent, suppuration, sores, pustules, and respiratory infections (Hemalatha et al. 2014). The main active constituent Houttuynia exerts potent antibacterial effect against range of pathogenic organisms by adopting different mechanisms such as inhibition of interleukin-8 (IL-8) and C–C motif chemokine ligand 20 (Sekita et al. 2016). The water extract of HCT could effectively treat intracellular bacterial infections caused by Salmonella in the RAW macrophage cell line. The stability and efficacy of HCT water extract were ascertained by analyzing virulence reduction activities in Salmonella Typhimurium–infected BALB/c mice (Kim et al. 2008).

Gegen Qinlian (GQ) oral liquid

GQ decoction, a classic TCM formulation, is composed of four herbs, namely, Puerariae Radix, Scutellaria baicalensis Georgi, Coptis chinensis Franch, and Glycyrrhizae Radix et Rhizoma Praeparata cum Melle, and was observed to inhibit Salmonella, Enterococcus, and E.coli with MIC value of 41.7 µg/mL, 20. 83 µg/mL, and 62.5 µg/mL, respectively (Liang et al. 2022).

Shorea robusta Gaertn (SRG)

In Indian traditional medicine, Shorea robusta L. is used for ameliorating diverse ailments. Traditionally, the chief bioactive constituent, the gum resin, is used to control diarrhea, dysentery, gonorrhea, and as astringent. A survey-based study conducted over the tribals of Birhore, Jharkhand region in India, revealed that local communities were consuming 7–10 tender leaves of S. robusta along with black pepper (Piper nigrum L.) for 7 days two times in a day to control long-term fever. Chattopadhyay et al. (2018) investigated the scientific reasons of anti-salmonella potential of methanolic and aqueous leaf extracts of S. robusta against 40 multi-drug-resistant (MDR) clinical isolates of S. Typhi, and it was found to have promising results with MIC and MBC of the extracts observed to be 256–450 μg/mL against S. Typhi isolates, while MBC was ≤ 512–1024 μg/mL.

Conclusion

Globally, the mounting incidence and prevalence rate of S. enterica infections coupled with the rapid emergence of MDR strains are posing a daunting challenge that necessitates the exploration of alternative and innovative strategies. Due to the exponential upsurge in the number of resistant strains against conventional antibiotics, major emphasis is being laid on discovery of novel antibiotics to cater for the severity. In the aspect of the antibiotic resistance crisis, phytochemicals derived from medicinal plants arise as valuable allies in the continuing battle against Salmonella enterica. The present review underpins and exemplifies the substantial contribution of phytochemicals, harbored from medicinal plants inhabiting diverse geographical regions and climatic conditions, in the fight against S. enterica infection. Several studies demonstrating the anti-salmonella potential of plant extracts and purified compounds with rich structural and functional attributes offer a promising avenue for developing phytodrugs as an alternative to combat S. enterica infection. Moreover, the drastic transition from traditional medicine to evidence-based herbal formulations marks a promising trend. Further studies shall be directed at tapping the novel medicinal chemistries as herbal formulations against antibiotics against drug-resistant pathogens. The development of these formulations, from clinical trials to commercialization, embodies a step towards integrating traditional wisdom with modern healthcare practices. The development of plant-derived drugs not only adheres to the principles of sustainable development but also provides solutions for sapping the challenges posed by drug-resistant strains. Further, the herbal formulations have been highlighted as adjuvants making the drug-resistant bacteria sensitive to the antibiotics. Thus, antibiotic-herbal adjuvant combinatorial therapy has the potential to be used as an effective therapy to overcome antibiotic resistance by bacteria. With persisting advancement in the field of phytodrugs, the development of innovative and persuasive phytochemical-based therapies can pave the way to crucial breakthroughs in extenuating the worldwide repercussions of Salmonella infections.