Role of membrane proteins in bacterial resistance to antimicrobial peptides

Several natural antimicrobial peptides (AMPs), including the novel semisynthetic lipoglycopeptide antibiotics telavancin, dalbavancin, and oritavancin, have been approved for clinical use to address the growing problem of multiple antibiotic-resistant Gram-positive bacterial infections. Nevertheless, the efficacy of these antibiotics has already been compromised. The SARS-CoV-2 pandemic led to the increased clinical use of all antibiotics, further promoting the development of bacterial resistance. Therefore, it is critical to gain a deeper understanding of the role of resistance mechanisms to minimize the consequential risks of long-term antibiotic use and misuse. Here, we summarize for the first time the current knowledge of resistance mechanisms that have been shown to cause resistance to clinically used AMPs, with particular focus on membrane proteins that have been reported to interfere with the activity of AMPs by affecting the binding of AMPs to bacteria.