Abstract
Antibiotics are miracle drugs that can cure infectious bacterial diseases. However, their utility is challenged by antibiotic resistant bacteria emerging in clinics and straining the modern medicine and our ways of life. Certain bacteria such as Gram-negative (Gram(- )) and Mycobacteriales species are intrinsically resistant to most clinical antibiotics and can further gain multidrug resistance through mutations and plasmid acquisition. These species stand out by the presence of an additional external lipidic membranes (the outer membrane, OM) that are composed of unique glycolipids. Although formidable, the OM is a passive permeability barrier that can reduce penetration of antibiotics but cannot affect intracellular steady-state concentrations of drugs. The two-membrane envelopes are further reinforced by active efflux transporters that expel antibiotics from cells against their concentration gradients. The major mechanism of antibiotic resistance in Gram(-) pathogens is the active efflux of drugs, which acts synergistically with the low permeability barrier of the OM and other mutational and plasmid-borne mechanisms of antibiotic resistance.
