Topoisomerases are the target of gyrase inhibitors such as quinolones, ribosomes are the targets of chloramphenicol and streptomycin, and penicillin-binding proteins are important for biosynthesis of peptidoglycan, which makes up the bacterial cell wall and is the target of -lactam antibiotics. Mechanisms of Gram-negative antibiotic resistance include (i) acquisition of enzymes that modify or destroy antibiotics, such as aminoglycoside-modifying enzymes and extended spectrum -lactamases and carbapenemases, (ii) acquisition of enzymes that alter bacterial antibiotic targets, such as lipid A-modifying enzymes conferring resistance to colistins, and (iii) acquisition of mutations in bacterial targets such as topoisomerases, ribosomes, penicillin-binding proteins, and outer membrane porins that alter antibiotic efficacy or uptake ( 2). Since fewer new antibiotics targeting Gram-negative bacteria are in development and organisms that resist all or most clinically useful antimicrobials are already being isolated, drug-resistant infections due to Gram-negative bacteria represent a significant health care concern for the future. These bacteria use a wide variety of mechanisms to resist antimicrobial killing, many of which are carried on mobile genetic elements transmitted to other bacteria ( 2). Recently Gram-negative bacteria with resistance to commonly used antibiotics, including quinolones, colistins (polymyxins), carbapenems, cephalosporins, and other β-lactam antibiotics, have been isolated from humans with increasing frequency. Therefore, the outer membrane can be thought of as an important, regulated organelle protecting the bacteria from toxicity, while allowing the uptake of valuable compounds utilized by the organisms for growth. The outer membrane barrier can be regulated by environmental signals, including antibiotics, and damage to the outer membrane can be both sensed and repaired. In addition to protecting the organism from toxicity, the outer membrane efficiently allows the uptake of soluble nutritional components through specific beta-barrel protein channels, termed “porins,” which are outer membrane protein components with a distinct beta-barrel structure largely only found elsewhere in the outer membrane of eukaryotic mitochondria. Therefore, one major function of the outer membrane is to both promote antimicrobial resistance and to interpret bacterial signals from membrane-damaging agents, including antibiotics. The outer membrane likely evolved, in part, to protect the bacteria against damage from antibiotics produced within multispecies microbial communities, where they function in microbial communication and competition.

This commentary provides context about this interesting paper and discusses the prospects of utilizing increased knowledge of outer membrane biology to develop new antibiotics for antibiotic-resistant Gram-negative bacteria. These investigators demonstrate that toxic oxygen radicals, such as those found in host tissues, regulate outer membrane permeability by altering the outer membrane porin protein channels to regulate the influx of oxygen radicals as well as β-lactam antibiotics. Brett Finlay at the University of British Columbia (J. Recently, significant research progress has been made in understanding the biogenesis, regulation, and functioning of the outer membrane, including a recent paper from the laboratory of Dr. The Gram-negative outer membrane is an important barrier that provides protection against toxic compounds, which include antibiotics and host innate immune molecules such as cationic antimicrobial peptides.

Gram negative bacteria