Antibiotics, Efflux, and pH

Abstract

Bacterial metabolism affects the effectiveness of antibiotics. Bacterial metabolism is linked to the ability of an antibiotic to be bactericidal or bacteriostatic because a bacterium can metabolize carbohydrates that affect its pH and its ability to use the proton motive force (PMF). When the pH is low, there is more availability of protons that can help to power the proton motive force needed for the efflux of antibiotics. Antibiotics increase the internal pH of a bacterial cell, but when the external pH is low or acidic, the lethality of the antibiotics dwindles. Adding an efflux inhibitor (EI) can block the efflux of antibiotics; however, the pH also affects the effectiveness of the efflux inhibitor. At a low pH the efflux inhibitor cannot block the efflux of antibiotics. This is important for the effectiveness of EIs to block efflux in acidic bacterial environments such as in the stomach or in the small intestines where the pH is highly acidic and low. However, in the colon the pH is highly alkaline and higher leading to a lesser availability of protons, in which the bacterial cells must rely on carbohydrate metabolism to expel any noxious agent such as an antibiotic via the ATP activation of the ABC transporter. As a consequence, for an efflux inhibitor to be effective the pH and the metabolism of carbohydrates to power the ABC transporter must be considered in the design of potential efflux inhibitors. This commentary will offer support for the arguments made in the article, Reducing bacterial antibiotic resistance by targeting bacterial metabolic pathways and disrupting RND efflux pump activity, by presenting the results of experiments that prove the gene inhibition of the AcrAB-TolC subunits of AcrB and TolC as a potent and effective EI design.

L-glutamine sensitizes Gram-positive-resistant bacteria to gentamicin killing

“…For instance, ΔpH mediated aminoglycoside uptake ( 36 ), and alkaline conditions increased antibiotic efficacy ( 37 ). Thus, pH imbalance may contribute to antibiotic resistance via inducing changes in the antibiotic efflux systems and proton motive force ( 28 , 38 , 39 ). Nigericin/excess K + or (NH 4 ) 2 SO 4 was used to disrupt ΔpH.…”