Key role of poly-γ-dl-glutamic acid in immune evasion and virulence of Staphylococcus epidermidis

Abstract

Coagulase-negative staphylococci, with the leading species Staphylococcus epidermidis, are the predominant cause of hospital-acquired infections. Treatment is especially difficult owing to biofilm formation and frequent antibiotic resistance. However, virulence mechanisms of these important opportunistic pathogens have remained poorly characterized. Here we demonstrate that S. epidermidis secretes poly-γ-DL-glutamic acid (PGA) to facilitate growth and survival in the human host. Importantly, PGA efficiently sheltered S. epidermidis from key components of innate host defense, namely antimicrobial peptides and neutrophil phagocytosis, and was indispensable for persistence during device-related infection. Furthermore, PGA protected S. epidermidis from high salt concentration, a key feature of its natural environment, the human skin. Notably, PGA was synthesized by all tested strains of S. epidermidis and a series of closely related coagulase-negative staphylococci, most of which are opportunistic pathogens. Our study presents important novel biological functions for PGA and indicates that PGA represents an excellent target for therapeutic maneuvers aimed at treating disease caused by S. epidermidis and related staphylococci.

Bacterial strategies of resistance to antimicrobial peptides

“…R. Soc. B 371: 20150292 in contrast to PIA, PGA does not directly facilitate biofilm formation [64,66], although the PGA biosynthesis cap operon is upregulated in biofilms of S. epidermidis [67,68].…”

“…PGA is found only in Gram-positive bacteria, mainly in Bacillus species and coagulase-negative staphylococci including S. epidermidis [64,65]. In addition to its role in resisting ingestion by leucocytes, PGA provides protection from LL-37, HBD-3 and dermcidin, similar to PIA.…”

The structure of PghL hydrolase bound to its substrate poly‐γ‐glutamate

“…The role of the c-PGA capsule as a fundamental virulence factor has been extensively established both for the Gram-positive B. anthracis and for the Gram-negative Francisella tularensis, both representing major biological threats [4][5][6][7][8]. Staphylococcus epidermidis also uses c-PGA to evade host defences and its presence might be linked to persistence of some infections [9]. The majority of c-PGAproducing bacteria, including S. epidermidis, secrete a heterochiral polymer composed of D-and L-Glu isomers (c-DL-PGA) that surrounds bacteria without covalent attachment [1,9].…”

“…Staphylococcus epidermidis also uses c-PGA to evade host defences and its presence might be linked to persistence of some infections [9]. The majority of c-PGAproducing bacteria, including S. epidermidis, secrete a heterochiral polymer composed of D-and L-Glu isomers (c-DL-PGA) that surrounds bacteria without covalent attachment [1,9]. In contrast, the pathogen B. anthracis synthesises a 100% D-Glu polymer (c-D-PGA) covalently anchored to the peptidoglycan layer by the unusual c-glutamyltranspeptidase CapD [10].…”

“…Understanding how c-PGA-degrading enzymes work is an important goal. In B. anthracis, F. tularensis and S. epidermidis, enzymatic degradation of the c-PGA capsule or lack of c-PGA synthesis has been shown to drastically mitigate bacterial virulence in animal models, allowing infected organisms to develop appropriate immune responses by neutrophils [5,9,[12][13][14]. In the long term, such results will contribute to the development of a therapeutic derivative of PghP-like enzymes as a tool against persistent infections caused by c-PGA-producing pathogenic bacteria.…”