A Review on the Resistance of Probiotic Microorganisms to Antibiotics
Aranyak Ram1, Dibyojyoti Bhattacharjee1, Sk Mahbub Alam1, Snehasis Jana2, Rohan Pal3*
1Department of Pharmacology, Global College of Pharmaceutical Technology, Krishnanagar, Nadia,
West Bengal, India.
2Department of Pharmaceutical Technology, Maulana Abul Kalam Azad University of Technology,
Haringhata, Nadia, West Bengal, India.
3Assistant Professor, Department of Pharmacology, Global College of Pharmaceutical Technology, Krishnanagar, Nadia, West Bengal, India.
*Corresponding Author E-mail: pal.rohan1995@gmail.com
ABSTRACT:
Live microorganisms that give the host health benefits when taken in pre-determined doses are known as Probiotics. Probiotics are gaining popularity worldwide and are widely used in food and medicine. Consumption of probiotics is increasing with further in-depth research on the relationship between intestinal flora and host health. Most people pay more attention to the function of probiotics but ignore their potential risks, such as infection and antibiotic resistance transfer to pathogenic microbes. Some probiotic strains harbour genes for resistance that could potentially be shared with harmful bacteria in the gut, contributing to the overall problem of antimicrobial resistance. This horizontal gene transfer is one mechanism by which antibiotic resistance (AMR) could arise due to probiotics. This horizontal gene transfer is successfully carried out by, Conjugation, Transformation, Transduction processes. Probiotics, live bacteria offering gut health benefits, are generally safe. However, some potential risks exist. Certain probiotic strains may carry genes for antibiotic resistance on plasmids, transferable DNA. This raises the concern of creating multi-drug resistant pathogens. Additionally, some individuals with weakened immune systems or underlying health conditions may experience side effects like bloating or gas. To mitigate these risks, choosing probiotics with well-researched strains and documented safety profiles is crucial. Consulting a healthcare professional before starting probiotics, especially if immunocompromised or with chronic conditions, is also recommended. In this document we attempted to list few of the antibiotic resistance (AMR) which propagate through probiotics.
KEYWORDS: Probiotics, Lactobacillus, Antibiotic Resistance, Horizontal gene transfer, β-lactam.
INTRODUCTION:
Probiotics are Existing microorganisms that give the host health benefits when taken in sufficient and pre-determined doses1.
Probiotics have been shown to provide a multitude of health benefits, including the management of gastrointestinal disorders, improvement of intestinal immune response, prevention of allergic reactions, protection of the cardiovascular system, antitumorigenic effects, and a hypo-choesterolemic property2–7. These benefits have been demonstrated by numerous experimental studies. In many therapeutic settings, probiotics offer a novel and efficient substitute for conventional preventive and treatment plans8. Because of this, probiotics and their products are currently the subject of intense study worldwide. A large number of probiotic products have emerged in the dairy, food, pharmaceutical, and fermentation sectors, where they are typically well-liked by consumers9.
People are starting to pay more attention to probiotic safety concerns as they become more widely used. Some probiotics may be consisting negative impacts on the health of host, including immune weaker conditions, D-lactic acidosis, bacteremia, and antibiotic resistance gene transfer, according to a few investigations. Probiotics provide the greatest short-term danger to patients because they can spread infectious illnesses like endocarditis by ingesting probiotic dairy beverages and capsules10–15. Cannon, Lee, Bolanos, along with Danziger [2005] conducted among the most thorough research on the impact of infections of probiotic, Lactobacillus was shown to be often associated with endocarditis as well as bacteremia, and the death rate for Lactobacillus infections was about 30% Additional species of Lactobacillus, Enterococcus, and Leuconostoc have the potential to induce bloodstream infections and bacterial endocarditis. Furthermore, it has been shown that after receiving multispecies probiotics, patients with acute pancreatitis showed an increased incidence of intestinal ischemia but no decreased risk of infectious complications16–20. Lactobacilli and bifido-bacteria have been linked to an amount of 0.05–0.4% of instances of infectious bacteremia as well as endocarditis in affluent nations, proving that probiotics are no longer safe supplements to enteral nutrition21.
Now a days, probiotics have the potential to become resistant to antibiotics when subjected to prolonged selection pressure. Lactobacillus naturally possesses resistance to bacitracin, vancomycin, kanamycin, and β-lactam22–24. Antibiotic-resistant genes are stored in probiotics and can be passed to pathogens or gut flora either horizontally or vertically. It has been suggested that these possible risk factors are crucial markers for assessing probiotics25–27.
In this review briefly introduces antibiotics resistance in probiotics, which includes mechanisms, risks and strategies of genes [such as tet, cat, blaZ, ermB, cfxA, van, etc.] and probiotics [Lactobacillus] and their typical cases. It also discusses potential risks and action for coping with probiotic resistance.
ROLE BEHIND ANTIMICROBIAL RESISTANCE DUE TO PROBIOTICS:
Probiotic bacteria have been added to animal and human feed, which has aided their entry into the food chain. They have been reported to precipitate in microbial resistance and provide a long-term ingestion risk28, 29. Multiple modes of action for the resistance were suggested and supported by the kind of antibiotic, the drug's target site, the yeast strain and bacteria or the capacity to connect chromosomal mutation and plasmids30. Initially, it was assumed by molecular research that gene transfer and mutation may be the mechanisms of action. The probable mechanism for the transfer of antibiotic-resistant genes from probiotics to the human normal microbiota has been suggested despite experiments completed in 1959 on the translocation of Shigella AB-R genes to the E. coli and considerable subsequent dissimilitude among resistance genes discovered in beta-lactamases and aminoglycosides inactivating enzymes28.
Furthermore, the validity of the gene transfer idea was shown by the AMR genes and antibiotic resistance have commonalities, as do the sequences present in both gram +ve and gram -ve human pathogenic microbes31.
Figure 1. Mechanism of probiotics in maintaining gut health.
Conjugation [direct cellular link], transduction [phage-associated], and also transformation between bacterial species reduced the spread of defective genomes between species via integrins or transposons32, 33. Additionally, investigations on people have shown that use of probiotics and gut microbiota in humans has a 25-fold increased prevalence of HGT. It can thus be regarded as a reservoir of resistance genes34. Moreover, AMR of the oral cavity microbiota is primarily linked to resistance to streptococcal therapy and resistance to tetracycline via the translocation of tet[O], tet[M], tet[W] and tet[Q] genes35, 36.
Figure 2. Probiotics acquiring antibiotic resistance.
Additionally, bacteria that include both mobile and intrinsic genetic elements are clearly capable of transferring antibiotic resistance genes horizontally and are essential to the emergence of multi-resistant yeasts and bacteria3, 37. Subsequent research revealed that AMR genes may be accumulated by human or animal normal microbiota and subsequently transferred to other strains currently present in the colon, such as pathogenic or intrinsic microbes38. However, study of the transferred tetracycline genes for resistance revealed that these AMR genes originated in the human gut microbiome, either directly or indirectly39, 40. The presence of antibiotic resistance genes in aquatic animals enabled the reciprocal gene transfer across pathogenic microorganisms and probiotics as a result of their usage in aquaculture30. Pathogenic bacteria like Clostridium difficile colonise when natural microbiota is disrupted after antibiotic therapy for infectious diseases. Antibiotics that have the least negative effects on the gut are preferred because resistant gens strains are more likely to congregate in the colon and can spread AB-R genes to the existing microbes41.
MECHANISMS OF PROBIOTIC RESISTANCE:
The use of probiotics in dietary and medical applications is highlighted. Probiotics primarily work by altering the micro ecological environment of the flora, engaging with pathogens to exclude them, regulating the immune system, producing functional materials [such as fatty acids, enzymes, amino acids, and bacteriocins], nutrients altering the microbiota-gut axis, influencing metabolism, and other functions. Probiotics such as Lactobacillus acidophilus (L. acidophilus) ATCC53103, Bifidobacterium infantis of stain ATCC156967, and L. reuteri [DSM 17938 and ATCC PTA 4659] might help to cure or prevent intestinal illness42.
A variety of species of Bifidobacterium and Lactobacillus [Bifidobacterium infantis, Lactobacillus rhamnosus, L. plantarum, L. acidophilus, etc.] improved the barrier function of host epithelial cells by strengthening the mucus layer and tightening the connections between enterocytes43, 44. Additionally, various probiotics, including Enterococcus faecium, B. animalis subsp. Lactis, and L. casei Q14, improved energy harvest by generating vitamins, amino acids, short-chain fatty acids, and secondary bile acids. Other strains of E. faecalis and Bifidobacterium, such as B. bifidum, B. breve, and B. longum13.
Figure 3. Antibiotic resistance of probiotics and its mechanism.
POTENTIAL RISKS AND STRATEGIES OF PROBIOTICS:
Table 1. Depicts the potential risks and strategies of probiotics
|
Potential risks |
Factors |
References |
|
Infectivity and pathogenicity: When the host's intestinal barrier is injured and immune suppression occurs, probiotics may spread from the GI tract to intestinal or extraintestinal tissue such as spleens, local lymph nodes, or livers. This might lead to systemic infections. |
45 |
|
|
Detrimental metabolism action: Certain strains of Enterococcus and Lactobacillus are being demonstrated to release amino acid decarboxylase, which may convert tyrosine and histidine to tyramine and histamine. This is proven by the very high quantity of 4070 nmol/mL histamine on MRS broth. Certain dosages of histamine or tyramine can induce heart failure, urticaria, migraines, hypertension, brain haemorrhage, and stomach cramps in vulnerable consumers. |
13, 46 |
|
|
Allergic reaction: Studies have shown that probiotics raise the chance of developing atopic sensitization, asthma or rhinitis, and other allergic reactions. |
47, 48 |
|
|
Overabundance of immune response: Some probiotics, including L. casei, have the ability to balance the Th1/Th2 ratio and trigger the Th1 response; nevertheless, an overabundance of Th1 stimulation may worsen autoimmune illnesses. |
49 |
|
|
Transfer of antibiotic-resistant genes: Mice carrying genes resistant to vancomycin. |
49 |
|
|
Strategies |
Dosage: Immune responses can be variably modulated by varying doses. In mice injected with E. coli, L. plantarum G83 from giant panda faeces improved intestinal flora and decreased inflammation. The lower dosage (1.0 × 108 CFU/d) and moderate dose (1.0 × 109 CFU/d) were typically better than the high dose (1.0 × 1010 CFU/d). [86]. Single-strain probiotics administered at low dosages (3-6×109 CFU/d) and for a short duration (< 8 w) were found to be more effective than placebo in relieving IBS indications and patient quality of life. |
50 |
|
Formulation: A particular formulation should be taken into consideration with regard to a certain health issue since changes in probiotic formulations may greatly impact the efficacies among various receivers. |
51 |
|
|
Delivery route: In humans, a variety of methods are employed, including injectable, subcutaneous, oral, and nasal delivery. Among these, taking probiotics orally is a desirable alternative for the treatment of allergic and anti-inflammatory illnesses. Probiotics can be administered subcutaneously or via the nose to treat health issues such as the common cold in humans. |
52 |
|
|
Probiotics can be labelled with antibiotic susceptibility, which makes it easier to combine probiotics and antibiotics for treatment |
23 |
|
|
Probiotics can be used with cell-free supernatants, this can address both safety and antibiotic resistance. |
53 |
LACTOBACILLUS AS PROBIOTICS:
The most popular probiotic is Lactobacillus, which is also the oldest known type of bacteria. It belongs to the gram-positive, non-motile, non-sporing, microaerophilic bacilli family of lactic acid bacteria, which is characterised by the absence of oxidase and catalase54. In addition to phenotypic identification by biochemical reactions, this group is often identified at the molecular level through SrRNA amplification and sequencing. Identification methods including RAPD [Randomly Amplified Polymorphic DNA], ARDRA [Amplified Ribosomal DNA Restriction Analysis] and PFGE [Pulsed-Field Gel Electrophoresis] are currently becoming more and more important because of the strain-specific advantageous characteristics of this bacterium55, 56. Lactobacilli are bacteria that thrive on complex media by saccharoclastic and fermentative routes. When they ferment, they release lactate and, seldom, acetate as byproducts57
It is essential for preserving the equilibrium of the gut microbiota following antibiotic use. Moreover, lactobacilli are utilised to treat allergy disorders, infectious diarrhoea, lactose intolerance, cancer progression, and to strengthen the host immune system58. Inflammatory bowel illness, Crohn's disease, diarrhoea caused by Clostridium difficile, and antibiotic-associated diarrhoea can all be significantly reduced by consuming Lactobacillus sp. and other probiotic formulations59, 60. In cases of C. difficile infection, drug exposure causes microbial disturbance, which can be remedied by faecal transplantation treatment61. In the penicillinase period, Alexander Fleming identified the essential ways for the improvement of antibiotic resistance as a result of overuse or incorrect use of antibiotics and its repercussions62. One of the main reasons antibiotics don't work for infections is the spread of drug resistance among bacteria. The key query is: Can bacteria convey all types of resistance? Bacteria can develop acquired or innate resistance to antibiotics.
Every strain belonging to a bacterial species or genus have intrinsic resistance. Among the gram-ve bacteria, Proteus species, Serratia species, and Burkholderia species are a few outliers. Although there are occasional outliers when the gene for resistance is flanked by an insertion sequence, increasing dispersion, intrinsic resistance has very little probability of spreading across bacteria. Prior exposure to antibiotics does not cause intrinsic resistance, and the likelihood of it spreading is minimal. It is mostly caused by several efflux pumps Intrinsic resistance is also influenced by the cell wall's impermeability and the absence of specific drug targets63.
On the other hand, bacteria can develop acquired or atypical resistance primarily through two mechanisms: Acquiring exogenous DNA or chromosomal mutation through integrins or transposons. When compared to mobile genetic elements, the incidence of chromosomal mutation translocation is lower64. The primary mechanism of gene transfer among bacteria is lateral or horizontal gene transfer [HGT]65. Three main processes in bacteria promote horizontal gene transfer [HGT]: transformation mediated by bare DNA, transduction triggered by bacteriophages, and conjugation by direct bacterial cell-to-cell contact66. The bacterium will proliferate locally by spreading its resistance to the nearby flora after it has developed resistance through these ways. MDR transporters, which are efflux pumps that can move both medicines and other substances, are another way that bacteria might become resistant to antibiotics. HorA and HorC are one of the existences in Lactobacillus, which are proton motive [dependent on force] hop excretion transporters33.
Table 2. Some probiotics with their function
|
Species |
Physiological functions |
Direct effects |
|
Lactobacillus gasseri |
Improving seasonal allergies |
Modulated immune function |
|
L. paracasei |
Improving ocular symptoms in allergic rhinitis |
Improved allergic rhinitis |
|
L. acidophilus |
Increasing the number and
vitality of probiotics in |
The anticancer activity of
Lactobacillus acidophilus and L. |
|
L. rhamnosus |
Regulating intestinal flora,
preventing diarrhea, and |
Reducing the risk of diarrhoea from 13.9% to 5% |
|
L. casei and Enterococcus faecalis |
Improving immune function and gut microbiota |
Reducing the diarrhoea rate and mortality |
ANTIBIOTIC RESISTANCE IN LACTOBACILLUS:
Antibiotic potential pattern is species-specific in Lactobacillus. AB-resistance has been found in Lactobacillus is isolated from the faces of the healthy volunteers by Drago67, 68. It was also discovered that some Lactobacillus acidophilus, L. casei, L. crispatus, L. plantarum and isolates were resistant to tetracyclines and/or macrolides. Furthermore, numerous Lactobacillus bacteria resistance genes (such as erm, tet, etc.) are transferable and can transfer to other Lactic Acid Bacteria as well as pathogenic bacteria, creating a risk to humans69, 70. The ability to transmit plasmids with wild-type erythromycin and tetracycline resistance from L. plantarum DG522 to E. faecalis JH2-2 in the GIT of rats was demonstrated by Jacobsen et al71.
Table 3. Species wise antibiotic resistance in Lactobacillus
|
Sl. No. |
Antibiotics |
Lactobacillus Species |
Reference |
|
1. |
Β- Lactam Antibiotics |
L. Casei |
72-76, 77 |
|
L. plantarum |
|||
|
L. curvatus |
|||
|
L. sakei |
|||
|
L. fermentum |
|||
|
L. helveticus |
|||
|
L. reuteri |
|||
|
L. rhamnosus |
|||
|
2. |
Glycopeptide |
L. rhamnosus |
23, 82-92 |
|
L. acidophilus |
|||
|
L. delbruekii |
|||
|
L. paracasei |
|||
|
L. salivarius |
|||
|
L. plantarum |
|||
|
L. crispatus |
|||
|
L. johnsonii |
|||
|
L. acidophilus |
|||
|
L. delbrueckii |
|||
|
3. |
Aminoglycosides |
L. plantaram |
98 |
|
4. |
Tetracycline |
L. sakei |
33, 34, 94, 102, 104, 108, 109 |
|
L. paracasei |
|||
|
L. plantarum |
|||
|
L. reuteri |
|||
|
L. paracasei |
Resistance on Cell Wall acting Antibiotics:
Research indicates that Lactobacillus species have a general susceptibility to several inhibitors of cell wall production, including β-lactamase inhibitors and penicillin’s [ampicillin, oxacillin, and piperacillin]. Nevertheless, greater resistant to cephalosporins [cefoxitin, ceftriaxone, and cephalotin and cefuroxime]. Penicillin’s, particularly penicillin G, are, nevertheless, becoming increasingly resistant to lactobacilli can be uses probiotics; L. casei in fermented milk Dahi‖; L. rhamnosus, L. plantarum, L. reuteri derived from cheese; L. delbrueckii bulgaricus subsp. derived from Chinese yogurts; and lactic acid bacteria of fermented milk in Burkina Faso or India72–76.
Regarding β-lactam AB, Lactobacilli commonly shows penicillin sensitivity, while they have significant resistance to cephalosporins. As an example, Gong et al. reported using L. casei resistant to cephalosporin as a vaginitis therapy regimen77. There is a possibility that cephalosporinase activity exists in cephalosporin-resistant L. casei. Strains of Lactobacilli isolated from particular kind of cheese, named Parmigiano-Reggian displayed penicillin G resistance in research by Belletti et al73. As far as we are aware, there have been not any results indicating that the β-lactam type of drugs resistance-transferability in lactic acid bacteria. Antibiotic genes have been transferred to other bacteria in the environment, as evidenced by the presence of penicillin-binding proteins, two more strains that are resistant, and the lack of β-lactam resistance genes. In spite of penicillin resistance, another research showed that ampicillin resistance was also observed in a few lactobacilli [Lactobacillus sp. strains that were not species-identified and L. plantarum strains] that were isolated from yogurt and other milk products74. Additionally, fermented fish, fermented milk in India, and fermented foods and drinks in Nigeria were shown to have ampicillin-resistant lactobacilli78–80. Other species of ampicillin-resistant lactobacilli were recovered from a variety of products. These include L. plantarum in fermented-sausage, L. casei from yogurt [dahi], L. curvatus and L. sakei, L. fermentum and L. helveticus from fermented fruits and vegetables64, 81. It has been found that point mutation within the pbp genes, that synthesise the proteins Pbp1a, Pbp2a, and/or Pbp2x that bind penicillin., which are targets of β-lactam antibiotics, confer resistance to ampicillin. in L. reuteri. Because the pbp genes are found on chromosomes, this resistance is thought to be non-transferable. It has also been showed that lactobacilli, mainly Lacto rhamnosus, which is isolated from dairy products, among those various dairy products display resistance to oxacillin and cephalosporins73.
b) Glycopeptide:
Vancomycin intrinsic resistance has been shown by Lactobacillus. As vancomycin is considered to be the best treatment for clostridium difficile colitis, research interest on vancomycin resistance in Lactobacillus is growing very rapidly. As a result, L. rhamnosus GG was used in addition to the standard antibiotic course to treat recurrent C. difficile infections. It is considered as non-transferable as it is an intrinsic resistance mechanism82. Enzymes linked to D alanyl-D alanine-ligase are thought to be responsible for vancomycin resistance of Lactobacillus83. When the medication gets into contact to the precursors of peptidoglycans within the cell wall of bacteria, yet another process is set in motion. Vancomycin inhibits the the process of peptidoglycan receptor polymerization in susceptible bacteria by attaching itself to the pentapeptide's D-alanine terminus. Nevertheless, in Lactobacillus along with Other resistant microorganisms’ substitute D-alanine with D serine. or D lactate Which inhibits vancomycin. binding and encourages the formation of cell walls84. VanX, encodes D-ala D-aladipeptidase, is present in some Lactobacillus species and is necessary for cell wall synthesis 40. Lactobacillus lacks the vanA, vanB, and vanC genes in contrast to Enterococcus, which is resistant to vancomycin85. However, the potential significance of Lactobacillus vanX's role in drug resistance as well as mobility needs further research86. According to Johnson et al., this might be attributed to the suppression of vancomycin resistance in L. acidophilus produced by plasmid-mediated transfer. Hamilton-Miller and Shah discovered vancomycin resistance in L. delbruekii strains, perhaps due to differing identification procedures87.
The ability of Lactobacillus to withstand the existence of antibiotics without passing on resistance genes is the main characteristic of its intrinsic resistance. Therefore, because Lactobacillus vancomycin resistance replenishes the gut flora, it can help prevent antibiotic-associated diarrhoea in certain cases23. The majority of Lactobacillus species possess innate resistance to glycopeptides, this is frequently attributed to the incorporation of D-Alanine-D-Lactate in the peptidoglycan instead of the D-Ala-D-Ala dipeptide. The inability to transmit vancomycin-resistance genes from L. rhamnosus to a vancomycin sensitive enterococcal gene reaffirmed the safety of the Lactobacillus strains utilised as probiotics in terms of vancomycin resistance. This resistance varies from enterococcal resistance, which is dependent on an existence of vanA, vanB, or vanC acquired genes72, 88, 89. Vancomycin resistance was discovered in many probiotic strains of Lactobacillus rhamnosus; however the resistance foundation of Lactobacillus spp. remains unknown, raising questions regarding their function as probiotics90. In a similar way it was determined that L. paracasei, L. salivarius, and L. plantarum all have innate resistance to vancomycin91. Nevertheless, another research revealed that L. crispatus, L. johnsonii, L. acidophilus, and L. delbrueckii subsp. bulgaricus have evolved mechanisms of resistance to vancomycin mater92.
Resistance on protein synthesis inhibitors:
The majority of Lactobacillus species are resistant to aminoglycosides [streptomycin, gentamicin, kanamycin, neomycin, ] but vulnerable to antibiotics that inhibit protein synthesis [tetracycline, erythromycin, clindamycin, & chloramphenicol]93. Lactobacillus separated from various fermented foods have been observed to be resistant to aminoglycosides. These include L. plantarum from fermented vegetables, Lactobacillus pentosus from naturally fermented olives, L. bulgaricus and L. paracasei from yogurt, L. helveticus, L. delbrueckii subsp. lactis, Lactobacilli casei, L. fermentum and L. pentosus from cheese, L. plantarum from dairy products, Lactobacilli fermentum, L. helveticus, L. namurensis, and L. plantarum from vegetables that have been fermented, L. brevis, L. fermentum, and L. paracasei L. paracasei subsp. from fermenting sausages and L. plantarum, L. casei, and L. paracasei from fermented fish. Finally, it was observed that aph[3′]-III along with additional resistance genes were found on the identical plasmid from E. faecium SZ109, confirming horizontal gene transfer94. Changes in cellular permeability and a lack of cytochrome-mediated transport of electrons, which allows antibiotic absorption, are two proposed reasons of intrinsic resistance to certain aminoglycosides90. However, the major cause of resistance is enzymatic antibiotic alteration by phosphotransferases [APH], adenyltransferases [ANT], along with acetyltransferases [AAC9], whose expressing genes are frequently found on transposons and plasmids95. As previously stated, erythromycin, clindamycin, tetracycline, and chloramphenicol can all affect the majority of Lactobacillus species. However, lactobacilli separated out from a variety of fermented foods have also been found to have strains resistant to these drugs. Chloramphenicol resistance was found in Lactobacilli derived from Chinese yogurts L. plantarum, L. helveticus, L. fermentum, and L. namurensis have all been identified from fermented vegetable foods in China96. It has been proven that strains of Lactobacillus spp. derived from cheese, dairy products, Chinese fermented vegetable foods, fermented meats and a range of fermented foods are resistant to erythromycin96, 97.
a) Aminoglycosides:
Aminoglycosides, especially kanamycin and gentamicin resistance in lactic acid bacteria, ought to be considered very carefully as gentamicin is a major first-choice medication for treating infections in both people and animals. Most of the resistance to gentamicin may be due to misuse of the drug. Jaimee et al. discovered that L. plantaram has the aminoglycoside-modifying genes aac (60) Ie-aph (200) Ia and aph(30)IIIa, which demonstrate kanamycin and gentamicin and resistance, correspondingly98. However, other data indicate that Aminoglycoside impedance transfer is yet absent in Lactobacillus. This does not imply that it is not transferable, since individuals of Enterococcus have already been shown to harbor a conjugative transposon that may indicate the transfer of gene of antibiotic resistance99. The list of microbes that need to be assessed should include those that have spread resistance to this drug. This debate is influenced by the worry that genes encoding virulence factors and genes resistant to antibiotics may be transmitted from the probiotic bacteria strains to pathogens or vice-versa within the GI system. In a pilot research, resistance to the antibiotic’s streptomycin, aztreonam, gentamicin, and ciprofloxacin varied between batches of five commercially available probiotic dietary supplements100. In order to allay future worries, it is imperative that every probiotic be tested for resistance patterns immediately before to large-scale industrial manufacturing. Apart from generalized transfer studies in lactic acid bacteria, the risk of resistance gene transfer among Lactobacillus sp. has not yet been thoroughly investigated101. As mentioned by Guo et al., filter-mating tests should be the main method used to assess the transferability of drug resistance102. On the overall, resistance to antibiotics, if not transferred, can be regarded a positive phenomenon, especially among powerful bacterial pathogens during combined therapy with antibiotics. According to current papers, the worry about the safe use of probiotics may be reduced by the non-transferability of resistance among them103.
b) Tetracycline:
Tetracycline resistance is one of the most studied resistance determinants in Lactobacilli, with the finding of 11 resistance coding genes, including tet[O], tet[K], tet[W], tet[S], tet[Q], tet[M], tet[36], tet[L], tetZ, and tet[O/W/32/O/W/O] [194, 195]. The bulk of these genes—especially tet[L] and tet[K]—are plasmid-coded, and some—such as tet[O], tet[M], and tet[Q], - are plasmid and chromosomally coded. The resistance mechanism is provided by either ribosome protection or efflux pumps33. It was shown that tet[M] and tet[K] may be found in very few Lactobacillus species even in absence of phenotypic tetracycline resistance34. However, tet[M] genes of Lactobacilli are not transferable, according to research by Guo et al.102. Before choosing a probiotic strain, these investigations highlight the possibility of resistance in tetracycline transmission in LAB, which has to be further investigated. Several lactobacilli species are isolated from Chinese fermented vegetable meals, cheese, and fermented vegetables were found to be resistant to clindamycin.In lactobacilli isolated from a range of fermented foods, including African fermented millet porridge, Chinese fermented vegetable foods, cheese, dairy products, from many kinds of fermented foods, pickles, fermented vegetables, fermented meat, and pickles, tetracycline resistance was founded94. It was discovered that the most frequently observed resistance, erm[B] for erythromycin resistance and tetM and tetS genes [encoding ribosomal protection proteins in tetracycline resistance], mediated acquired tetracycline resistance also resitance in, chloramphenicol, clindamycin, and erythromycin in lactobacilli derived from fermented foods. acquired resistance in lactobacillus isolated from fermented meals to erythromycin, clindamycin, tetracycline, and chloramphenicol94,104.
The most often recognised resistance genes in lactobacilli isolated from a range of meals were discovered to be tetM and tetS [encoding ribosomal protective proteins for tetracycline resistance] and erm[B] [erythromycin resistance], which were found to be the mediating factors of acquired resistance to tetracycline, clindamycin, erythromycin, and chloramphenicol in lactobacilli isolated from fermented foods. The CAT [plasmid encoding chloramphenicol acetyltransferase] gene was found to be the second most frequently observed resistance gene105. Recent research has demonstrated that lactobacillus possessed tetracycline resistance genes other than tetM and tetS genes. These include the ribosomal protection protein-encoding tet[W] gene, which can be found in lactobacilli in dairy products and the tetL efflux gene, which is found in lactobacilli from fermented meat. Tet[M] and Tet[S] resistance genes were found on plasmids and chromosomes in several Lactobacillus species isolated from various fermented food products. As demonstrated by Comunian et al. [2010], tet[M] expression, like tetracycline resistance genes in E. coli, requires strict control based on antibiotics. Furthermore, the findings with two strains of L. sakei derived from an Italian cheese made from raw milk, where tetM was discovered inside transposon-like sequences, are supported by this discovery88, 106,107. Tet[M] was discovered on the Tn916 chromosome in L. paracasei samples derived from water buffalo mozzarella. All strains had the identical MIC value of 32μg/ml. It was also discovered in L. plantarum M345 [plasmid pLFE1] derived from raw-milk cheese, and its transposon may be transmitted to other LAB97. However, it has found that tet[W] gene that is carried through plasmid, which is most showing in animal and human intestinal bacteria, did not transfer the tetracycline resistance gene in L. reuteri to bacteria in the gut microbiota of humans108. L. paracasei was derived from the unpasteurized milk and natural whey starter cultures that are used in the production of the conventional Italian cheese Mozzarella di Bufala Campana. the conjugative transposon Tn916—an 18-kbp genetic element containing the genetic determinant for tetracycline resistance tetM—occurred. It was capable of horizontal interspecies transfer to the opportunistic pathogen Enterococcus faecalis109.
c) Metronidazole:
Metronidazole inhibits anaerobes selectively. Prior research has demonstrated that Lactobacilli exhibit metronidazole resistance due to an innately decreased sensitivity to the antibiotic. Metronidazole functions by obstructing electron transport pathways or by interfering with the phosphoroclastic pathway110. Once more, as one of the options for treating C. difficile infections, metronidazole resistance is an additional benefit of Lactobacillus30.
The majority of Lactobacillus species exhibit inherent resistance to aminoglycosides, metronidazole, glycopeptides, norfloxacin, gentamicin, enoxacin, pefloxacin, nalidixic acid, and coprofloxacin; additionally, they are resistant to folic acid synthesis inhibitors, such as co-trimoxazole, trimethoprim, and sulphamethoxazole They are, nevertheless, susceptible to the following medications: penicillin G, quinupristin/dalfopristin, linezolid, ampicillin, chloramphenicol, ampicillin, streptomycin, clindamycin, erythromycin, tetracycline, and more susceptibility to bacitracin (polypeptide antibiotic) varies69.
Resistance on DNA replication inhibitors:
a) Quinolones:
Lactobacilli tend to be fundamentally resistant against quinolones, which include ciprofloxacin and nalidixic acid. Intrinsic resistance to ciprofloxacin was not found to be associated with mutations in the QRDRs of parC and gyrA, as was the case in Gram-positive bacteria; thus, intrinsic resistance could have been caused in intrinsic characteristics including permeation, cell wall structure or an efflux mechanism65,69.
Resistance on folic acid synthesis inhibitors:
It has also been shown that the folate auxotrophic lactobacilli possess an inherent resistance to trimethoprim and sulphonamides. In some circumstances, sulfamethoxazole or trimethoprim phenotypic determination of susceptibility of lactic acid bacteria in a few culture media may not be coherent, because certain antagonistic medium components like as thymidine and p-aminobenzoic acid (PABA) may conflict with the antibiotic activity. Other resistance mechanisms found in lactobacilli derived from fermented foods include impermeability of the alternative metabolic pathways, cell wall, trimethoprim-insensitive dihydrofolate reductase (DHFR) overproduction, and transferable DHFRs that are insensitive to trimethoprim65, 69.
CONCLUSION:
Published studies suggest that bacteria naturally present in fermented foods may serve as a significant reservoir of antibiotic resistance genes, potentially transferring these genes to intestinal microbiota upon ingestion. Our findings indicate the presence of glycopeptide and chloramphenicol resistance genes in lactobacilli from fermented foods, highlighting the need for molecular characterization of these genes in both fermented foods and probiotics. Furthermore, their ability to transfer antibiotic resistance genes must be considered.
The antibiotic resistance crisis possesses a destructive impact on human and animal health. Increasing the severity, incidence, and cost of infectious disease management led to further studies in this area. Efflux pumps, mutations, and gene acquisition (gene transfer or transduction) are counted as the most important mechanisms for the microorganisms involved in the occurrence of antibiotic resistance. Probiotics, which include specific strains of bacteria and yeast, have come under scrutiny for their possible role in AMR.
The development of probiotics for human consumption remains in its infancy. The potential risks of probiotics, a global public health problem, deserve extensive attention in the fields of food and medicine. Gene transfer between probiotics and normal microbiota via mobile genetic elements was made possible when the probiotic microorganisms occupy available niches in the GIT. Moreover, during antibiotic treatment, which establishes an imbalance in the microbiota, colonization of pathogenic bacteria is escalated. It provides an environment to transfer genetic content among available microorganisms such as pathogenic bacteria, probiotics, and the normal microbiota. HGT among existing microorganisms (donors or recipients) leads to resistance toward a wide range of antibiotics. The development of probiotics for human consumption remains in its infancy. The potential risks of probiotics, a global public health problem, deserve extensive attention in the fields of food and medicine.
Molecular studies reported sequence similarities between resistance genes in different bacteria and identical sequences in gram-positive and gram-negative bacteria, which shed light on the transfer of mutant genetic content across the mentioned microorganisms. Although different strains of probiotics carry specific resistance genes, they are capable of transferring to other microorganisms. This review supports the double-edged impact of probiotic consumption, and taking adequate precaution for the prevention of probiotics’ wide-spreading side effects is recommended.
CONFLICT OF INTEREST:
The authors have no conflicts of interest regarding this investigation.
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Received on 16.04.2024 Revised on 02.07.2024 Accepted on 14.08.2024 Published on 18.12.2024 Available online on December 21, 2024 Asian J. Pharm. Tech. 2024; 14(4):330-340. DOI: 10.52711/2231-5713.2024.00054 ©Asian Pharma Press All Right Reserved
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