A New Role of Metformin as an Efflux Pump Inhibitor in Klebsiella Pneumonia

Abstract

Respiratory tract infections caused by Klebsiella pneumoniae are frequently associated with high mortality and morbidity rates. Treatment of these infections is usually difficult due to the emergence of multiple resistances to antibiotics. Multidrug efflux pumps are greatly involved in antibiotic resistance in Gram-negative bacteria including Klebsiella pneumoniae. In the current study, efflux activity was observed in 93.75% of Klebsiella pneumoniae clinical isolates by the qualitative acridine orange agar method. This finding was further confirmed genotypically by polymerase chain reaction that showed the presence of efflux genes AcrA, AcrB, TolC and mdtk in these isolates. The ability of metformin to inhibit efflux activity was compared with the reference efflux pump inhibitors verapamil and ascorbic acid. Metformin was more active than ascorbic acid and less active than verapamil. Up to our knowledge, this is the first report that shows that metformin has an efflux pump-inhibiting activity in Klebsiella pneumoniae.

Promising FDA-approved drugs with efflux pump inhibitory activities against clinical isolates of Staphylococcus aureus

“…Furthermore, Baiomy et al [64] study tested the EPI activities by two methods; EtBr-Cartwheel method and determining the decrease in the antibiotics MICs, while, our study used four methods in which our results were confirmed by RT-PCR unlike Baiomy et al [64] study. In another study; Abbas et al [73] study, metformin significantly reduced tetracycline and ciprofloxacin MICs in MDR of Klebsiella pneumonia isolates.…”

“…Thus, the repurposing of the drugs as the FDA-approved ones as it saves the costs and shortens the long time needed for the development of new antimicrobials [68]. This concept has been applied recently in many studies [59,64,[69][70][71][72][73][74].…”

“…Therefore, in our study, the FDA-approved drugs as diclofenac sodium, domperidone, GTN and metformin were investigated for their EPI activities against S. aureus at their 1/8 MICs. Similarly, many previous studies have used the 1/4 or 1/8 of the MIC of the tested compounds [59,64,[72][73][74]. Due to the use of 1/8 MIC of the tested compounds that had no effect on the bacterial growth, the possibility of the emergence of resistant mutants is much less than that in case of antibiotics that exert a stress on the bacterial growth.…”

Discovery of Broad‐Spectrum Repurposed Drug Combinations Against Carbapenem‐ResistantEnterobacteriaceae(CRE) Through Artificial Intelligence (AI)‐Driven Platform

“…ENT646 is a hypervirulent K. pneumoniae (hvKp) isolate, [38] an example of the alarming emergence of "superbugs" due to the increasing convergence of hypervirulence and carbapenem resistance in K. pneumoniae. [38][39][40] The initial pool of 12 drugs was selected from three groups: 1) mainstay antibiotics essential for treating CRE infections, such as MEM and polymyxin B (PB); [8,9,41] 2) drug sensitizers, such as efflux pump inhibitor metformin; [42] and 3) repurposed drugs reported with antibacterial activity (Table 1). IDentif.AI assesses three clinically relevant drug concentrations.…”

The Action of Efflux Pump Genes in Conferring Drug Resistance to Klebsiella Species and Their Inhibition

“…Grimsey et al 67 demonstrated the efficacy of chlorpromazine and amitriptyline as EPIs to restore the antibacterial activity of the given antibiotics and inhibit the AcrB-mediated efflux. Abbas et al 68 investigated the potential inhibition activity of novel EPI (metformin) on AcrAB and Mdtk efflux pumps of K. pneumoniae. Their reports suggest the use of metformin over the existing EPIs ascorbic acid and verapamil in restoring the efficacy of the antibiotics.…”