How innate immunity proteins kill bacteria and why they are not prone to resistance

Abstract

Recent advances on antibacterial activity of peptidoglycan recognition proteins (PGRPs) offer some insight into how innate immunity has retained its antimicrobial effectiveness for millions of years with no frequent emergence of resistant strains. First, PGRP can bind to multiple components of bacterial envelope (peptidoglycan, lipoteichoic acid, and lipopolysaccharide). Second, PGRP simultaneously induces oxidative, thiol, and metal stress responses in bacteria, which individually are bacteriostatic, but in combination are bactericidal. Third, PGRP induces oxidative, thiol, and metal stress responses in bacteria through three independent pathways. Fourth, antibacterial effects of PGRP are enhanced by other innate immune responses. Thus, emergence of PGRP resistance is prevented by bacteriostatic effect and independence of each PGRP-induced stress response, as PGRP resistance would require simultaneous acquisition of three separate mechanisms disabling the induction of all three stress responses. By contrast, each antibiotic has one primary target and one primary antibacterial mechanism, and for this reason resistance to antibiotics can be generated by inhibition of this primary mechanism. Manipulating bacterial metabolic responses can enhance bacterial killing by antibiotics and elimination of antibiotic-tolerant bacteria, but such manipulations do not overcome genetically encoded antibiotic resistance. Pathogens cause infections by evading, inhibiting, or subverting host immune responses.

Keywords: Antibacterial resistance; Metal stress; Oxidative stress; Peptidoglycan recognition proteins; Thiol stress.

Fig. 1. PGRP induces oxidative, thiol, and metal stress through independent pathways, which individually are bacteriostatic and together become bactericidal

PGRP induces oxidative stress through a block in respiratory chain, which diverts electrons from respiratory chain NADH oxidoreductases to O₂ and generates H₂O₂. Production of H₂O₂ depends on increased supply of NADH from glycolysis and tricarboxylic acid (TCA) cycle. PGRP also induces thiol stress (depletion of thiols) and metal stress (increase in intracellular free Zn²⁺ through influx of extracellular Zn²⁺), which are mostly independent of oxidative stress and of each other (Kashyap et al. 2014, 2017).