Penicillin-Binding Protein 1a Promotes Resistance of Group B Streptococcus to Antimicrobial Peptides

Abstract

Evasion of host immune defenses is critical for the progression of invasive infections caused by the leading neonatal pathogen, group B streptococcus (GBS). Upon characterizing the factors required for virulence in a neonatal rat sepsis model, we found that a surface-associated penicillin-binding protein (PBP1a), encoded by ponA, played an essential role in resistance of GBS to phagocytic clearance. In order to elucidate how PBP1a promotes resistance to innate immunity, we compared the susceptibility of wild-type GBS and an isogenic ponA mutant to the bactericidal components of human neutrophils. The isogenic strains were found to be equally capable of blocking complement activation on the bacterial surface and equally associated with phagocytes and susceptible to oxidative killing. In contrast, the ponA mutant was significantly more susceptible to killing by cationic antimicrobial peptides (AMPs) of the cathelicidin and defensin families, which are now recognized as integral components of innate host defense against invasive bacterial infection. These observations may help explain the sensitivity to phagocytic killing and attenuated virulence of the ponA mutant. This novel function for PBP1a in promoting resistance of GBS to AMP did not involve an alteration in bacterial surface charge or peptidoglycan cross-linking. While the peptidoglycan polymerization and cross-linking activity of PBPs are essential for bacterial survival, our study is the first to identify a role for a PBP in resistance to host AMPs.

Comprehensive Proteomic and Metabolomic Signatures of Nontypeable Haemophilus influenzae-Induced Acute Otitis Media Reveal Bacterial Aerobic Respiration in an Immunosuppressed Environment

“…Penicillin-binding protein 1A mediates bacterial membrane stability and has been shown to promote resistance to antimicrobial peptides in Streptococcal species (147). Our observation suggests that penicillin-binding protein 1A may provide resistance against the host cathelicidin (15kDa protein A-like) observed during AOM.…”

Differing mechanisms of surviving phagosomal stress among group BStreptococcusstrains of varying genotypes

“…Both strains, for example, had »2-fold upregulation of ponA, which encodes the penicillin-binding protein 1a that was linked to phagosomal stress resistance in a prior study by protecting GBS against cationic antimicrobial peptides. 26 The cyl operon, which includes cylE, produces a pore-forming b-hemolysin/cytolysin (bH/C) and a carotenoid pigment that helps protect against reactive oxygen species. A previous study showed that a cylE deletion mutant does not produce either the bH/C or pigment and is more susceptible to both oxidative and macrophage killing.…”

Host Defense Peptides in Wound Healing

“…Microorganisms have also developed ways to escape direct killing by human host defense peptides (171)(172)(173)(174), which emphasizes their important and ancient role in the innate immune system (172). However, resistance mechanisms are generally related to the direct killing of bacteria and are not comparable to the resistance mechanisms of conventional antibiotics.…”