The role of bacterial transport systems in the removal of host antimicrobial peptides in Gram-negative bacteria

This review describes how Gram-negative bacteria use efflux pumps as a mechanism of resistance against antimicrobial peptides (AMPs), including the efflux of AMPs to the extracellular space and the internalization of AMPs to the cytoplasm followed by proteolytic digestion. We have summarized the experimental evidence for the involvement of efflux in AMP resistance and combined this with analysis of the structure of the efflux systems involved and address the significant remaining open challenges and questions in the field Antibiotic resistance is a global issue that threatens our progress in healthcare and life expectancy. In recent years, antimicrobial peptides (AMPs) have been considered as promising alternatives to the classic antibiotics. AMPs are potentially superior due to their lower rate of resistance development, since they primarily target the bacterial membrane ('Achilles' heel' of the bacteria). However, bacteria have developed mechanisms of AMP resistance, including the removal of AMPs to the extracellular space by efflux pumps such as the MtrCDE or AcrAB-TolC systems, and the internalization of AMPs to the cytoplasm by the Sap transporter, followed by proteolytic digestion. In this review, we focus on AMP transport as a resistance mechanism compiling all the experimental evidence for the involvement of efflux in AMP resistance in Gram-negative bacteria and combine this information with the analysis of the structures of the efflux systems involved. Finally, we expose some open questions with the aim of arousing the interest of the scientific community towards the AMPs-efflux pumps interactions. All the collected information broadens our understanding of AMP removal by efflux pumps and gives some clues to assist the rational design of AMP-derivatives as inhibitors of the efflux pumps.