Atomic-Resolution Structures and Mode of Action of Clinically Relevant Antimicrobial Peptides

Abstract

Global rise of infections and deaths caused by drug-resistant bacterial pathogens are among the unmet medical needs. In an age of drying pipeline of novel antibiotics to treat bacterial infections, antimicrobial peptides (AMPs) are proven to be valid therapeutics modalities. Direct in vivo applications of many AMPs could be challenging; however, works are demonstrating encouraging results for some of them. In this review article, we discussed 3-D structures of potent AMPs e.g., polymyxin, thanatin, MSI, protegrin, OMPTA in complex with bacterial targets and their mode of actions. Studies on human peptide LL37 and de novo-designed peptides are also discussed. We have focused on AMPs which are effective against drug-resistant Gram-negative bacteria. Since treatment options for the infections caused by super bugs of Gram-negative bacteria are now extremely limited. We also summarize some of the pertinent challenges in the field of clinical trials of AMPs.

Cathelicidin-derived antiviral peptide inhibits herpes simplex virus 1 infection

“…The cathelicidin family is one of the most important AMPs in the host immune defense system. So far, some of the cathelicidin-related drugs are undergoing clinical trials, indicating that cathelicidins have great potential to be developed as new antimicrobial drugs as alternatives to traditional antibiotics and medicines (Steinstraesser et al, 2011 ; Wang et al, 2019 ; Mookherjee et al, 2020 ; Díez-Aguilar et al, 2021 ; Bhattacharjya et al, 2022 ; Talapko et al, 2022 ). It has been reported that cathelicidins possess many important activities such as broad-spectrum and high antibacterial activity, anti-inflammation, and tissue damage inhibition (Auvynet and Rosenstein, 2009 ; Nijnik and Hancock, 2009 ; Wuerth and Hancock, 2011 ; Choi et al, 2012 ; Kahlenberg and Kaplan, 2013 ).…”

A Novel Cryptic Clostridial Peptide That Kills Bacteria by a Cell Membrane Permeabilization Mechanism

“…Previous, circular dichroism (CD) studies showed that in the presence of a cell membrane-mimicking detergent, Intestinalin formed an α-helix ( 19 ). Therefore, we hypothesized that Intestinalin targets bacterial cell membranes similarly to other polycationic α-helical peptides ( 21 ).…”

“…It has been postulated that LTAs form a polyanionic ladder that helps cationic AMPs traverse the cell membrane of Gram-positive bacteria ( 35 ). In Gram-negatives, the role of LTAs is overtaken by lipopolysaccharide and outer membrane proteins that attract AMPs to the bacterial surface ( 21 ). That is probably the case with Intestinalin (P30), as the peptide is highly active against Gram-negative pathogens.…”

LL-37: Structures, Antimicrobial Activity, and Influence on Amyloid-Related Diseases

“…The lipopolysaccharide (LPS) outer membrane (or LPS-OM) of Gram-negative bacteria serves as a permeability barrier that limits intra-cellular access of several antibiotics [ 35 , 36 , 37 , 38 ]. Interactions of cationic AMPs with anionic phosphates of LPS or lipid A can cause an efficient permeabilization of the LPS-OM barrier [ 39 , 40 , 41 , 42 ]. AMP-mediated disruption of the LPS-OM is pivotal in killing Gram-negative bacteria [ 39 , 40 , 41 , 42 ].…”