Diarrheal diseases represent a significant public health concern. Notwithstanding the considerable strides made in modern medicine and the plethora of strategies devised to curtail infection, the mortality rate associated with diarrheal diseases caused by bacteria has exhibited only a modest decline over time. Annually, gastroenteritis bacteria are responsible for billions of infections, with a high morbidity rate and a relatively high mortality rate [19] [20] .

In Benin, diarrhea represents one of the most significant causes of morbidity on a daily basis. As indicated by data from the Ministry of Health, diarrheal diseases are less fatal than malaria or anemia. However, they have a significant economic and public health impact on the population. As indicated by the World Health Organization (WHO), diarrheal diseases represent the second leading factor contributing to reduced life expectancy, with a reduction of 1.97 years following lower respiratory tract infections, which result in a reduction of 2.09 years. This fact cites diarrheal diseases among the causes of premature death in countries with a low sociodemographic index (SDI) [2] .

The most common bacteria associated with diarrhea, according to the Global Burden of Disease study, are Campylobacter spp., Shigella spp., Vibrio cholerae, non-typhoidal Salmonella, enterotoxigenic Escherichia coli (ETEC), enteropathogenic Escherichia coli (EPEC) and Clostridioides difficile. Globally, Shigella spp. [21] [22] , non-typhoidal Salmonella [23] [24] and Campylobacter spp. [25] [26] were the leading causes of diarrheal mortality [27] . The most recent data from the Institute of Health Metrics Evaluation (IHME) indicate that Campylobacter spp. is the most dangerous bacteria, followed by Shigella spp. and Vibrio cholerae across all age categories ( Figure 1 ). Nevertheless, Shigella spp. is responsible for most deaths in children under five years of age ( Figure 1 ). These observations are consistent with those of the Global Enteric Multicenter Study (GEMS). The findings of this study indicate a significant correlation between Shigella spp. and an elevated risk of mortality in children under five years of age [28] - [30] . It is the primary cause of mortality in regions with low and moderately low SDI, followed by Vibrio cholerae and non-typhoidal Salmonella ( Table 1 ) [31] . A substantial proportion of the global burden of diarrheal disease is attributable to death rates from diarrheagenic Escherichia coli, particularly in low SDI regions ( Table 1 ). Clostridioides difficile is the most under-recorded bacterial species associated with gastroenteritis and diarrhea worldwide. But it is mainly known for causing intestinal infections, often after the use of antibiotics, which can lead to symptoms such as severe diarrhea, abdominal cramps and, in serious cases, complications such as toxic megacolon. It is particularly prevalent in regions with a high socio-demographic index ( Table 1 ).

Interventions for diarrheal diseases can be divided into two categories: preventive and therapeutic. Preventive measures to reduce exposure to enteric pathogens include improvements to the quality of drinking and cooking water, the quantity of water available for personal and domestic hygiene, safe food storage, hand washing and the sanitary disposal of faecal waste. These may include wastewater

Note: the classification of bacteria by SDI region and from most to least recurrent bacteria in each SDI region. Source: IHME, November, 15^th 2023.

treatment by a filtration system or boiling or the use of water purification tablets to inactivate microbial pathogens [32] . Nevertheless, it is crucial to situate the water source at a safe distance from latrines.

Given that dehydration is the most common complication of the disease, therapeutic intervention is primarily focused on reversing this dehydration. This practice is fundamental to the treatment of pediatric patients. An oral rehydration solution (ORS) is employed for this purpose. The solution is composed primarily of sodium, chloride, and glucose. The global distribution of this solution has contributed to a reduction in the number of deaths among children caused by diarrhea [33] . The World Health Organization (WHO) recommends zinc supplementation in conjunction with oral rehydration therapy for children, given the considerable zinc losses that occur during childhood diarrhea. In Bangladesh, a combination of oral rehydration solution (ORS), zinc and vitamin A was found to be highly effective in reducing the number of deaths caused by diarrhea in children [34] . In instances of severe dehydration, which is frequently observed in hospital settings in tropical countries, intravenous fluid replacement is employed as a treatment modality [4] . An antibiotic is incorporated into the oral rehydration treatment regimen.

A meta-analysis of randomized controlled trials has demonstrated that antibiotic therapy is an effective intervention for reducing the duration of illness caused by bacteria. The current drugs used to treat diarrhea and gastroenteritis caused by bacteria are metronidazole (nitroimidazole), azithromycin (macrolide), ciprofloxacin (quinolone), amoxicillin/clavulanic acid (β-lactam) and ceftriaxone (β-lactam) [35] . The aforementioned pharmaceutical agents may be administered in combination, according to the physician’s diagnosis, with the objective of achieving the most favorable outcome [36] . In particular, quinolones (ciprofloxacin) remain efficacious in instances of Shigella spp. infections; however, due to the emergence of multidrug resistance, azithromycin represents a viable alternative [37] . In the case of Campylobacter infections, treatment within four days of the onset of symptoms may result in improved outcomes with gentamicin. However, it should be noted that azithromycin and erythromycin are already prone to multidrug resistance [38] . The majority of non-typhoidal Salmonella infections are self-limiting. Nevertheless, in view of the potential risk of bacteremia in specific patient groups, treatment may be warranted for those at high risk, including children under one year of age, adults over 60, and individuals with underlying immunodeficiency. Similarly, resistance to quinolones is now prevalent in the treatment of Campylobacter infections. In such cases, azithromycin may be a superior option [39] . Nutrition also plays a role in the treatment of foodborne bacterial disease. Nutritional support can be considered both a therapeutic and a preventive measure. Malnutrition is both a consequence and a risk factor for diarrheal disease [40] . Nutritional support during diarrhea and nutritional rehabilitation during convalescence enhance resistance and facilitate recovery from subsequent episodes of diarrhea [33] .

The ongoing prevalence of foodborne diseases attests to the persistent challenge of effectively controlling enterobacteria, despite advancements in prevention and treatment strategies. The principal concern pertaining to food-borne bacterial diseases is the rising incidence of bacterial resistance to antibiotics [41] . As indicated by data from the Institute for Health Metrics and Evaluation, the multidrug-resistant gastroenteritis bacteria that are responsible for the greatest number of deaths globally are Escherichia coli, Shigella spp., and non-typhoidal Salmonella ( Figure 2 ). E. coli, all categories combined, is the main cause of death due to antibiotic resistance with a rate of 57% (mean value 58,702.5) deaths in 2019. The second bacteria responsible for gastroenteritis causing the most deaths due to multi-resistance to antibiotics is Shigella spp. (33%); then in third position is non-typhi Salmonella (10%) ( Figure 2 ).

Fluoroquinolones, which have historically demonstrated efficacy against a diverse range of bacterial pathogens, are gradually exhibiting reduced activity against these organisms. A reduction in the susceptibility of non-typhoidal Salmonella to fluoroquinolones has been documented in multiple studies conducted in various African countries [42] - [47] . China and India are the countries most affected by fluoroquinolone-resistant non-typhoidal Salmonella ( Figure 3A ). An analogous situation has been observed in the case of Shigella spp. overseas.

In France, there has been a concerning increase in the proportion of Shigella sonnei that is multi-resistant to ciprofloxacin, third-generation cephalosporins and azithromycin [48] . In Bangladesh, fluoroquinolone-resistant Shigella spp. has been the second most common cause of childhood diarrhea from 2019 to 2021, after E. coli [49] . As illustrated in Figure 3B , the proportion of fluoroquinolone-resistant Shigella spp. strains are notably elevated in South Asia and South-East Asia, according to IHME statistics. Fluoroquinolone-resistant E. coli is the most widely distributed globally ( Figure 3C ). Moreover, it is among the most prevalent strains that accumulate antibiotic resistance ( Figure 4 ) [50] [51] . Aminopenicillins are the antibiotic class with the highest proportion of E. coli resistant globally, particularly in Africa and Asia, according to IHME ( Figure 4A ). Furthermore, the β-lactam resistance strain is predominantly distributed in Africa, Asia, and a few regions of Latin America ( Figure 4B ). This can be attributed to the ease with which the general population can access aminopenicillins. Third-generation cephalosporins, which are considered a mainstay for the treatment of severe infections, have already been associated with cases of resistance in bacteria such as E. coli ( Figure 4C ) [52] - [57] .

In Asia, the use of antibiotics in animal husbandry favors resistance to fluoroquinolones. in Africa, b-lactam antibiotics are the most widely used antibiotics by the population, with practices that are not recommended. on the other hand, in Europe, it is the resistance of bacteria such as shigella, caused by the use of macrolides, quinolones and cephalosporins in medicine, that is more prevalent. In America, a combination of animal husbandry and treatment techniques, combined with the medical use of different antibiotic families, does not reflect a different pattern than in other parts of the world. These different, albeit dissimilar, practices around the world are conducive to the emergence of multi-resistant strains, thanks to the transfer of resistance via mobile genetic elements between bacteria. All of this contributes to the increasing difficulty of treating bacterial infections, and the growing number of deaths caused by multi-resistant bacteria responsible for gastroenteritis ( Figure 2 ). In light of the gravity of the multi-resistant strain’s situation and its ramifications at the individual and collective levels, a number of recommendations have been put forth by scientific societies. One such recommendation is that of hand hygiene. This is the most straightforward method of preventing the transmission of multi-resistant bacteria, particularly within hospital settings. It is of the utmost importance that healthcare workers adhere to the established hygiene protocols [58] . Strict adherence to the aforementioned recommendations would prevent the transmission of multi-resistant strains by touch. It is as crucial for healthcare workers to practice hand hygiene as it is for any other individual in society. Nevertheless, all hygiene practices, from hand hygiene to environmental hygiene, are efficacious measures against the dissemination of pathogens. While hygiene is an effective method of preventing the transmission of microorganisms, it is not a panacea. The control of antibiotic acquisition by patients, for instance through the implementation of a prescription

requirement prior to the purchase of antimicrobials, may prove an effective strategy for the reduction of the emergence of multi-resistant strains [59] . Such a measure would also serve to mitigate a number of the adverse consequences associated with self-medication. It is also imperative to implement active surveillance for multidrug-resistant strains in healthcare facilities. In the course of routine analysis of clinical specimens, microbiological testing laboratories are obliged to include antimicrobial susceptibility testing in order to monitor the emergence of multidrug-resistant strains. It is recommended that an update of the strain repertoire be conducted in the event of the emergence of new multi-resistant strains [60] .

The emergence of new cases of fatal infections due to the accelerated development of bacterial resistance to antibiotics underscores the urgent need for the development of novel therapeutic compounds. The use of natural products for the treatment of illness is a practice that has been employed by humans for a considerable length of time. The majority of these products are derived from plants, animals, or microorganisms.

Fungi are cosmopolitan microorganisms that play a significant role in the biodegradation of organic matter. They are particularly endowed with a well-developed secondary metabolism. The compounds produced by this metabolic process are referred to as secondary metabolites [61] . These are typically produced by fungi at the conclusion of their life cycle or during the process of colonizing diverse habitats or under conditions of stress [62] . Polyketides and non-ribosomal peptides are the most commonly secondary metabolites described as possessing antibacterial activity.

Polyketides represent the largest and most structurally diverse class of fungal secondary metabolites. This impressive diversity is the consequence of the remarkable flexibility of polyketide synthases. The selection of carboxylic acid derivatives, control of polymer length, cyclisation or cleavage, as well as aromatization, oxidation, alkylation and glycosylation on polyketides produced by polyketide synthases results in a vast array of bioactive secondary metabolites. The class of metabolites in question comprises polyesters, polyphenols, macrolides (macrocyclic esters), polyenes and enediynes [63] . These are primarily produced by fungi of the genus Penicillium [64] . Notable examples include xanthoradones A and B, penipyranicin C and xanthoepocin. The potentiation of imipenem activity against MRSA by xanthoradones A and B was demonstrated by a reduction in the MIC value of imipenem from 16 μg/ml to 0.060 and 0.030 μg/ml, respectively [65] . Penipyranicin C is produced by Penicillium CAAM64, which was isolated from a hydrothermal source. It has demonstrated notable efficacy against gram-negative bacteria, particularly Enterobacter xiangfangensis and Pseudomonas aeruginosa [66] . Additionally, xanthoepocin has been identified as a potent agent against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterobacter faecium, with an MIC of 0.313 µg/ml. Xanthoepocin is produced by Penicillium ochrochloron CBS 123823 [67] . It should be noted that polyketides are also produced by other fungi. This is exemplified by rubeline anthraquinone, which is produced by Ramularia collo-cygn, an ascomycete fungus that causes Ramularia plant diseases. Rubeline has been demonstrated to exhibit activity against Bacillus subtilis and Enterococcus faecalis 1528, and the multi-resistant strain, methicillin-resistant Staphylococcus aureus [68] . An additional illustration of antibacterial metabolites derived from polyketides is eupenicinicol. Eupenicillicum spp., an endophytic filamentous fungus, was the source of eupenicinicol, which demonstrated antibacterial activity against E. coli with a minimum inhibitory concentration of 5 µg/mL [69] . Given their provenance and structural diversity, polyketides have been demonstrated to exhibit broad-spectrum antibacterial activity and are also capable of combating multi-resistant strains.

Non-ribosomal peptides represent one of the most diverse and complex classes of secondary metabolites observed in the living world. Ascomycota are the primary producers. The biosynthesis of these compounds does not involve the usual protein synthesis machinery; instead, it is carried out by multidomain enzymes known as non-ribosomal peptide synthases.

β-lactams represent the most extensively studied category of non-ribosomal peptides. β-lactams are among the most extensively studied fungal antibacterial metabolites. This family of secondary metabolites comprises penicillins and cephalosporins, which are produced by fungi of the genera Penicillium and Acremonium, respectively [70] [71] .

Other classes of antibacterial secondary metabolites produced by fungi are cyclic dipeptides, terpenoids and isoquinoline alkaloids.

Cyclic Dipeptides are ubiquitous secondary metabolites in biological systems. They have been described as one of the oldest classes of signalling molecules and have even been found in extraterrestrial meteorites [72] . They are formed by the bonding of two amino acids. The absence of free C- and N-terminal groups in their formula means that they are resistant to human digestion. This characteristic makes them attractive for the development of protein-based drugs. Many cyclic dipeptides display biological activities such as inhibition of microbial growth and human tumor cells. For example, a single fermentation of Aspergillus fumigatus produced cyclic dipeptides, most of which have antibacterial activity [73] .

Periconicin A and B are secondary metabolites that belong to the class of compounds known as diterpenes. Both compounds demonstrated antibacterial activity against a range of human bacterial pathogens, including S. aureus and Salmonella Typhimurium [74] . The majority of bioactive fungal terpenes and terpenoids discovered in recent years have been isolated from marine fungi and fungi associated with algae [75] . Isoquinoline alkaloids are formed from the amino acids tyrosine and methionine. The most recently described are spathulin A and B, both produced by P. spathulatum and active against both gram-positive and gram-negative bacteria. Spathulin B has been demonstrated to exhibit greater activity than spathulin A, with an MIC of 5 µg/mL on E. coli LMG15862 [76] .

The diverse range of antibacterial metabolites produced by fungi can be employed as a basis for the synthesis of semi-synthetic antibacterial compounds. This is exemplified by pyrridium indole dicationic, a synthetic antibacterial compound with MIC 250 µg/mL on E. coli. This compound has been shown to optimize the antibacterial activity of crude extracts of the secondary metabolite produced by A. niger from MIC 250 µg/mL, initially reducing the concentration to 50 µg/mL after combining pyrridium indole dicationic with MIC 250 µg/mL [77] . Taking into account all this research into antibacterial fungal secondary metabolites, the importance of exploring the fungal kingdom in the fight against multidrug-resistant bacteria is well established ( Table 2 ).