Synergistic effects of antibiotics and efflux pump inhibitors on multidrug-resistant Escherichia coli and Klebsiella pneumoniae

Abstract Aim The increasing prevalence of multidrug-resistant Escherichia coli and Klebsiella pneumoniae presents a critical threat to public health. As a first line of defence, efflux pumps promote antibiotic resistance among pathogens. This study aims to assess the potential of efflux pump inhibitors (EPIs) as adjuvants for enhancing antibiotic efficacy against resistant pathogens. Methods and results This research investigated antibiotic resistance patterns, antibiotic resistance genes, and the effects and expression profiles of efflux pump genes. The study examined bacterial responses to sub-inhibitory levels of antibiotics, both individually and in conjunction with the EPI. The real-time PCR/Quantitative PCR (qPCR) demonstrated that antibiotic exposure led to an upregulation of efflux genes in E. coli and K. pneumoniae, with significant strain-specific differences. The co-administration of EPI resulted in downregulation of efflux genes, indicating successful inhibition of the pumps. Gene expression analyses suggested that PAβN influences the regulation of efflux genes and may trigger oxidative stress responses mediated by global regulators. This implies that EPIs could directly and indirectly affect bacterial physiology. Conclusions The results highlight the therapeutic promise of EPIs in combating antibiotic resistance. This study underscores the complexity of efflux-mediated resistance and the need for integrated strategies to mitigate MDR in Gram-negative pathogens.