Targeting bacterial outer-membrane remodelling to impact antimicrobial drug resistance

• Published in: Trends in microbiology (Regular ed.) 2022-06, Vol.30 (6), p.544-552
• Main Authors: Rosas, Natalia C., Lithgow, Trevor
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - metabolism; Anti-Bacterial Agents - pharmacology; Antimicrobial agents; Antimicrobial resistance; Bacteria; Bacteria - metabolism; Bacterial Proteins - metabolism; carbapenem; Drug resistance; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drugs; Evolution; Membrane proteins; membrane remodelling; Membranes; Nutrients; outer membrane; phage therapy; Phages; Phenotypes; porin; Porins; Porins - genetics; Porins - metabolism; Protein turnover; Proteins
• ISSN: 0966-842X; 1878-4380
• DOI: 10.1016/j.tim.2021.11.002

The cell envelope is essential for survival and adaptation of bacteria. Bacterial membrane proteins include the major porins that mediate the influx of nutrients and several classes of antimicrobial drugs. Consequently, membrane remodelling is closely linked to antimicrobial resistance (AMR). Knowledge of bacterial membrane protein biogenesis and turnover underpins our understanding of bacterial membrane remodelling and the consequences that this process have in the evolution of AMR phenotypes. At the population level, the evolution of phenotypes is a reversible process, and we can use these insights to deploy evolutionary principles to resensitize bacteria to existing antimicrobial drugs. In our opinion, fundamental knowledge is opening a new way of thinking towards sustainable solutions to the mounting crisis in AMR. Here we discuss what is known about outer-membrane remodelling in bacteria and how the process could be targeted as a means to restore sensitivity to antimicrobial drugs. Bacteriophages are highlighted as a powerful means to exert this control over membrane remodelling but they require careful selection so as to reverse, and not exacerbate, AMR phenotypes. How porins are assembled into the bacterial outer membrane is now understood in molecular detail. We also have knowledge of the signals that dictate which porin-encoding genes are activated under specific environmental stimuli, including the presence of antimicrobial drugs. These signals change the protein-specific composition of the outer membrane, a process referred to as outer-membrane remodelling.The general mechanisms by which mutations and/or adaptations confer AMR phenotypes on bacteria are known. One of these mechanisms is outer-membrane remodelling. Its impact on AMR, particularly carbapenem resistance, is a central feature of several of the bacterial pathogens currently rated as being in urgent need of research and new treatments.New therapies are canvassed here and warnings around phage therapy, based on considerations of outer-membrane remodelling, are made clear.