Preliminary Investigation On The Mechanism Of Famotidine Synergistic Effect Of Rifamycin Antibiotics

With the spread of human-derived Acinetobacter baumannii(A.baumannii),animal-related infections are reported to increase year by year,among which livestock and poultry infections are the main ones in China,with chicken-derived and cattle-derived isolation rates accounting for a larger proportion and higher mortality rates,affecting the healthy development of the farming industry and causing great concern to veterinary workers.More seriously,the frequent occurrence of drug resistance in Gram-negative bacteria including A.baumannii has restricted the efficiency and life span of commonly used clinical antibacterial drugs,and the development of new antibiotic adjuvants is imminent.The group had found that compounds containing guanidine groups have the potential to potentiate antimicrobial drugs.In this study,tests were conducted based on the clinical drug famotidine containing guanidine groups in order to obtain safe and effective antibiotic adjuvants.The results of the study are as follows:Firstly,this study investigated the synergistic activity of famotidine.The results showed that famotidine had synergistic effects with rifamycin antibiotics(rifampicin,rifabutin,rifapentine,rifaximin),in which the fractional inhibitory concentration index with rifampicin was 0.1875.Famotidine significantly increased the antibacterial activity of rifampicin against A.baumannii,Salmonella typhimurium,Escherichia coli,Klebsiella pneumoniae,Pseudomonas aeruginosa,Shigella flexneri and reversed strain resistance.Among them,the best potentiation activity was found in A.baumannii,and the minimum inhibitory concentration of rifampicin could be reduced by more than 4096 times under the effect of sub-inhibitory concentration.Secondly,this study investigated the mechanism of action of the potentiating activity of famotidine.The results showed that famotidine promoted the intracellular entry of the antibacterial drug by disrupting the cell membrane of A.baumannii and inhibiting the expression of the membrane protein omp A gene,while causing dissipation of the plasma membrane potential and compensatory increase of the p H gradient,which eventually resulted in the accumulation of elevated levels of reactive oxygen species and intensified bacterial death.Famotidine also inhibited the efflux pump efflux level of A.baumannii,promoting the intracellular accumulation of the drug and increasing the antibacterial activity.Finally,this study investigated the safety and in vivo efficacy of the combination.The results showed that the complete blood count and blood biochemical indices of mice were within the reference safety range after continuous administration of 8.2 mg/kg or 24.4 mg/kg famotidine with 25 mg/kg rifampicin.In the infection models of rifampicin-sensitive and rifampicin-resistant strains of A.baumannii,both co-administration significantly increased the survival rate of Galleria mellonella and mice and significantly reduced the organ bacterial load of mice compared with rifampicin treatment alone.In general,this study revealed a novel role for famotidine,a clinical gastric acid inhibitor,in enhancing the antibacterial activity of rifamycin antibiotics.It also conducted preliminary research on famotidine’s synergistic mechanism and assessed the safety and effectiveness of famotidine in combination with rifampicin in animals.These findings indicate the potential of famotidine as a novel adjuvant of rifamycin antibiotics.