New understanding of multidrug efflux and permeation in antibiotic resistance, persistence, and heteroresistance

Antibiotics effective against Gram-negative ESKAPE pathogens are a critical area of unmet need. Infections caused by these pathogens are not only difficult to treat but finding new therapies to overcome Gram-negative resistance is also a challenge. There are not enough antibiotics in development that target the most dangerous pathogens and there are not enough novel drugs in the pipeline. The major obstacle in the antibiotic discovery pipeline is the lack of understanding of how to breach antibiotic permeability barriers of Gram-negative pathogens. These barriers are created by active efflux pumps acting across both the inner and the outer membranes. Overproduction of efflux pumps alone or together with either modification of the outer membrane or antibiotic-inactivating enzymes and target mutations contribute to clinical levels of antibiotics resistance. Recent efforts have generated significant advances in the rationalization of compound efflux and permeation across the cell envelopes of Gram-negative pathogens. Combined with earlier studies and novel mathematical models, these efforts have led to a multilevel understanding of how antibiotics permeate these barriers and how multidrug efflux and permeation contribute to the development of antibiotic resistance and heteroresistance. Here, we discuss the new developments in this area.

Automated summary

There is a critical need for antibiotics effective against Gram-negative ESKAPE pathogens. However, it is challenging to find new therapies and develop antibiotics that can overcome Gram-negative resistance. The lack of understanding of how to breach antibiotic permeability barriers of these pathogens is the major obstacle in the antibiotic discovery pipeline. Recent efforts have made significant advances in understanding compound efflux and permeation across the cell envelopes, providing insights into antibiotic resistance and heteroresistance development.