Famotidine Enhances Rifampicin Activity against Acinetobacter baumannii by Affecting OmpA.

The development of novel antibiotic adjuvants is imminent because of the frequent emergence of resistance in Gram-negative bacteria, which severely restricts the efficiency and longevity of commonly used clinical antibiotics. It is reported that famotidine, a clinical inhibitor of gastric acid secretion, enhances the antibacterial activity of rifamycin antibiotics, especially rifampicin, against Gram-negative bacteria and reverses drug resistance. Studies have shown that famotidine disrupts the cell membrane of Acinetobacter baumannii and inhibits the expression of the outer membrane protein ompA gene, while causing a dissipation of the plasma membrane potential, compensatively upregulating the pH gradient and ultimately increasing the accumulation of reactive oxygen species by leading to increased bacterial mortality. In addition, famotidine also inhibited the efflux pump activity and the biofilm formation of A. baumannii. In the Galleria mellonella and mouse infection models, the combination of famotidine and rifampicin increased the survival rate of infected animals and decreased the bacterial load in mouse organs. In conclusion, famotidine has the potential to be a novel rifampicin adjuvant, providing a new option for the treatment of clinical Gram-negative bacterial infections. IMPORTANCE In this study, famotidine was discovered for the first time to have potential as an antibiotic adjuvant, enhancing the antibacterial activity of rifamycin antibiotics against A. baumannii and overcoming the limitations of drug therapy. With the discovery of novel applications for the guanidine-containing medication famotidine, the viability of screening prospective antibiotic adjuvants from guanidine-based molecules was further explored. In addition, famotidine exerts activity by affecting the OmpA protein of the cell membrane, indicating that this protein might be used as a therapeutic drug target to treat A. baumannii infections.

Antimicrobial resistance in E. Coli of animal origin and discovery of a novel ICE mobile element in Northeast China.

BACKGROUND: Multidrug resistance in Enterobacteriaceae including resistance to quinolones is rising worldwide. The development of resistance may lead to the emergence of new transmission mechanisms. In this study, the collection of different E. coli was performed from animals and subjected to subsequent procedures including pulsed-field gel electrophoresis, micro-broth dilution method, polymerase chain reaction. Whole genome sequencing of E. coli C3 was performed to detect the affinity, antimicrobial resistance and major carriers of the isolates. RESULTS: A total of 66 E. coli were isolated and their antibiotic resistance genes, frequency of horizontal transfer and genetic environment of E. coli C3 were determined. The results showed there were both different and same types in PFGE typing, indicating clonal transmission of E. coli among different animals. The detection of antimicrobial resistance and major antibiotic resistance genes and the plasmid transfer results showed that strains from different sources had high levels of resistance to commonly used clinical antibiotics and could be spread horizontally. Whole-genome sequencing discovered a novel ICE mobile element. CONCLUSION: In summary, the antimicrobial resistance of E. coli in northeast China is a serious issue and there is a risk of antimicrobial resistance transmission. Meanwhile, a novel ICE mobile element appeared in the process of antimicrobial resistance formation.

Citric Acid Confers Broad Antibiotic Tolerance through Alteration of Bacterial Metabolism and Oxidative Stress.

Antibiotic tolerance has become an increasingly serious crisis that has seriously threatened global public health. However, little is known about the exogenous factors that can trigger the development of antibiotic tolerance, both in vivo and in vitro. Herein, we found that the addition of citric acid, which is used in many fields, obviously weakened the bactericidal activity of antibiotics against various bacterial pathogens. This mechanistic study shows that citric acid activated the glyoxylate cycle by inhibiting ATP production in bacteria, reduced cell respiration levels, and inhibited the bacterial tricarboxylic acid cycle (TCA cycle). In addition, citric acid reduced the oxidative stress ability of bacteria, which led to an imbalance in the bacterial oxidation-antioxidant system. These effects together induced the bacteria to produce antibiotic tolerance. Surprisingly, the addition of succinic acid and xanthine could reverse the antibiotic tolerance induced by citric acid in vitro and in animal infection models. In conclusion, these findings provide new insights into the potential risks of citric acid usage and the relationship between antibiotic tolerance and bacterial metabolism.

Transmission of human-pet antibiotic resistance via aerosols in pet hospitals of Changchun.

In recent years, aerosols have been recognized as a prominent medium for the transmission of antibiotic-resistant bacteria and genes. Among these, particles with a particle size of 2 µm (PM2.5) can directly penetrate the alveoli. However, the presence of antibiotic-resistant genes in aerosols from pet hospitals and the potential risks posed by antibiotic-resistant bacteria in these aerosols to humans and animals need to be investigated. In this study, cefotaxime-resistant bacteria were collected from 5 representative pet hospitals in Changchun using a Six-Stage Andersen Cascade Impactor. The distribution of bacteria in each stage was analyzed, and bacteria from stage 5 and 6 were isolated and identified. Minimal inhibitory concentrations of isolates against 12 antimicrobials were determined using broth microdilution method. Quantitative Polymerase Chain Reaction was employed to detect resistance genes and mobile genetic elements that could facilitate resistance spread. The results indicated that ARBs were enriched in stage 5 (1.1-2.1 µm) and stage 3 (3.3-4.7 µm) of the sampler. A total of 159 isolates were collected from stage 5 and 6. Among these isolates, the genera Enterococcus spp. (51%), Staphylococcus spp. (19%), and Bacillus spp. (14%) were the most prevalent. The isolates exhibited the highest resistance to tetracycline and the lowest resistance to cefquinome. Furthermore, 56 (73%) isolates were multidrug-resistant. Quantitative PCR revealed the expression of 165 genes in these isolates, with mobile genetic elements showing the highest expression levels. In conclusion, PM2.5 from pet hospitals harbor a significant number of antibiotic-resistant bacteria and carry mobile genetic elements, posing a potential risk for alveolar infections and the dissemination of antibiotic resistance genes.

Genetic characterization of MDR genomic elements carrying two aac(6')-aph(2″) genes in feline-derived clinical Enterococcus faecalis isolate.

Multidrug-resistant Enterococcus faecalis (E. faecalis) often cause intestinal infections in cats. The aim of this study was to investigate a multidrug-resistant E. faecalis isolate for plasmidic and chromosomal antimicrobial resistance and their genetic environment. E. faecalis strain ESC1 was obtained from the feces of a cat. Antimicrobial susceptibility testing was carried out using the broth microdilution method. Conjugation experiments were performed using Escherichia coli and Staphylococcus aureus as receptors. Complete sequences of chromosomal DNA and plasmids were generated by whole genome sequencing (WGS) and bioinformatics analysis for the presence of drug resistance genes and mobile elements. Multidrug-resistant E. faecalis ESC1 contained a chromosome and three plasmids. The amino acid at position 80 of the parC gene on the chromosome was mutated from serine to isoleucine, and hence the amino acid mutation at this site led to the resistance of ESC1 strain to fluoroquinolones. Eleven antibiotic resistance genes were located on two plasmids. We identified a novel composite transposon carrying two aminoglycoside resistance genes aac(6')-aph(2″). This study reported the coexistence of a novel 5.4 kb composite transposon and a resistance plasmid with multiple homologous recombination in an isolate of E. faecalis ESC1. This data provides a basis for understanding the genomic signature and antimicrobial resistance mechanisms of this pathogen.