Drug efflux deficiency promotes growth-bistability and target resistance masking among bacterial pathogens

From Q-bio

Previously, we outlined the conditions for growth-bistability among bacteria exposed to growth inhibitory antibiotics in the medium (Elf et al. (2006), Phys Rev Lett. 97:258104). In the special case of rapid equilibration between target-bound and free intracellular drug concentrations, we showed how growth bistability is favored by slow drug efflux, high-affinity target-binding and high target concentration. Drug tolerance among pathogens is often conferred by target resistance mutations, increased drug efflux efficiency and the emergence of drug degradation pathways. Here, we have described the interplay between, on one hand, drug efflux and drug degradation efficiency and, on the other, target resistance mutations. We have clarified the conditions under which small drug efflux efficiency, e.g. due to drug efflux pump inhibition, masks the growth stimulatory effects of a broad class of target resistance mutations, and validated this prediction experimentally. Target resistance masking and growth-bistability in the presence of antibiotics are closely linked phenomena, depending on two bacterial growth regimes. In the first, the dominating pathway for intracellular drug reduction is by bacterial growth. In the second, the dominating pathway is by drug efflux through the cell wall(s) and drug degradation. These findings suggest the existence of conditions under which a broad class of target resistance mutations are masked and do not confer a growth advantage in relation to wild type, irrespective of the external drug concentration. Under such conditions, the emergence and fixation of target resistance mutations would be very slow.