Antimicrobial Peptide Resistance Mechanisms of Human Bacterial Pathogens

Abstract

The critical role played by antimicrobial peptides (AMPs) in mammalian innate immunity is increasingly recognized. Bacteria differ in their intrinsic susceptibility to AMPs, and the relative resistance of some important human pathogens to these defense molecules is now appreciated as an important virulence phenotype. Experimental analysis has identified diverse mechanisms of bacterial AMP resistance including altered cell surface charge, active efflux, production of proteases or trapping proteins, and modification of host cellular processes. The contribution of these resistance mechanisms to pathogenesis is confirmed through direct comparison of wild-type bacteria and AMP-sensitive mutants using in vivo infection models. Knowledge of the molecular basis of bacterial AMP resistance may provide new targets for antimicrobial therapy of human infectious diseases.

Allosteric mechanism of signal transduction in the two-component system histidine kinase PhoQ

“…Two-component system sensor Histidine Kinases (HKs) are conserved signaling modules in bacteria responsible for sensing a myriad of environmental stimuli and orchestrating transcriptional responses along with their cognate transcription factors (Response Regulators, RR) ( Stock et al, 2000 ; Groisman and Mouslim, 2006 ). These sensors are generally implicated in environment sensing and are involved in multi-drug resistance ( Nishino et al, 2005 ; Hirakawa et al, 2003 ; Nizet, 2006 ) and as master regulators of virulence programing in pathogenic bacteria ( Thomas and Cook, 2020 ; Delauné et al, 2012 ). HKs are constitutive homodimers, which transmit signals through a series of intermediary domains to a cytoplasmic catalytic domain.…”

Expression and Roles of Antimicrobial Peptides in Innate Defense of Airway Mucosa: Potential Implication in Cystic Fibrosis

“…AMPs, being an important component of the innate immune system, constitute one of the early, rapid, nonspecific mechanisms by which the host immune system provides protection against infections (13). Studies using knockout mice and transgenic (Tg) expression systems have confirmed that AMPs play a major role in limiting microbial proliferation to skin and mucosal surfaces, therefore preventing spread to the deep tissues where serious infection may occur (14). AMPs are produced by epithelial cells of vertebrates as a first line of defense against microbial pathogens.…”

“…At these sites, infections are controlled by the innate defense responses that allow the host to maintain its integrity (12). Knockout mice and Tg expression systems have confirmed that AMPs play a central role in limiting microbial proliferation in various host sites, thus preventing spread to the deep tissues where serious infection may occur (14). AMPs are produced by epithelial cells of vertebrates as a first line of defense against microbial invaders and tend to exhibit intrinsic specificity for the encountered pathogens.…”

“…Moreover, some bacteria exposed to AMPs may evolve under selective pressures to develop resistance mechanisms. Even though the existence of these selective pressures are, evolutionarily speaking, quite old, human AMPs still possess a broad spectrum of effective activity against a diverse range of microorganisms (14).…”

“…Hence, a number of AMPs have failed approval by the FDA after reaching phase II clinical trials due to their short-half life and their poor physical-chemical properties (17). However, even with limitations, AMPs still possess a broad spectrum of potent antimicrobial activity (14). Another potential issue includes the cytotoxicity to mammalian cells when bactericidal concentrations are high.…”