Antibiotic Resistance and Regulation of the Gram-Negative Bacterial Outer Membrane Barrier by Host Innate Immune Molecules

Abstract

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. 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. Brett Finlay at the University of British Columbia (J. van der Heijden et al., mBio 7:e01238-16, 2016, http://dx.doi.org/10.1128/mBio.01541-16). 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. 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.

FIG 1

(Left) Diffusion through the outer membrane bilayer allows hydrophobic compounds like chloramphenicol to reach their intracellular targets, but porin activity is required for transport of β-lactam compounds across the outer membrane. (Right) A compound that permeabilizes the outer membrane or dysregulates porin selectivity may allow β-lactam transport and peptidoglycan targeting, broadening the efficacy of our current drug arsenal against Gram-negative bacteria.