Journal Article

Staphylococcus aureus Survives with a Minimal Peptidoglycan Synthesis Machine but Sacrifices Virulence and Antibiotic Resistance

Atilano, Magda L., Ligoxygakis, Petros, Sher, Xinwei, Roemer, Terry, Reichmann, Nathalie T., Hoiczyk, Egbert, Filipe, Sérgio R., Alves, Renato, Pinho, Mariana G., Reed, Patricia, Pereira, Pedro M., Pereira-Leal, José B.

2015

Overview

Many important cellular processes are performed by molecular machines, composed of multiple proteins that physically interact to execute biological functions. An example is the bacterial peptidoglycan (PG) synthesis machine, responsible for the synthesis of the main component of the cell wall and the target of many contemporary antibiotics. One approach for the identification of essential components of a cellular machine involves the determination of its minimal protein composition. Staphylococcus aureus is a Gram-positive pathogen, renowned for its resistance to many commonly used antibiotics and prevalence in hospitals. Its genome encodes a low number of proteins with PG synthesis activity (9 proteins), when compared to other model organisms, and is therefore a good model for the study of a minimal PG synthesis machine. We deleted seven of the nine genes encoding PG synthesis enzymes from the S. aureus genome without affecting normal growth or cell morphology, generating a strain capable of PG biosynthesis catalyzed only by two penicillin-binding proteins, PBP1 and the bi-functional PBP2. However, multiple PBPs are important in clinically relevant environments, as bacteria with a minimal PG synthesis machinery became highly susceptible to cell wall-targeting antibiotics, host lytic enzymes and displayed impaired virulence in a Drosophila infection model which is dependent on the presence of specific peptidoglycan receptor proteins, namely PGRP-SA. The fact that S. aureus can grow and divide with only two active PG synthesizing enzymes shows that most of these enzymes are redundant in vitro and identifies the minimal PG synthesis machinery of S. aureus. However a complex molecular machine is important in environments other than in vitro growth as the expendable PG synthesis enzymes play an important role in the pathogenicity and antibiotic resistance of S. aureus.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Animals / Anti-Bacterial Agents - pharmacology / Anti-Bacterial Agents - therapeutic use / Antibiotics / Bacterial Proteins - genetics / Bacterial Proteins - metabolism / Bacteriology / Cell Wall - drug effects / Cell Wall - metabolism / Cell Wall - ultrastructure / Colleges & universities / Confidence intervals / Drosophila melanogaster - genetics / Drosophila melanogaster - metabolism / Drosophila melanogaster - microbiology / Drug Resistance, Multiple, Bacterial / Enzymes / Experiments / Gene Deletion / Gene Expression Regulation, Bacterial - drug effects / Genomes / Host-Pathogen Interactions - drug effects / Insect Proteins - genetics / Insect Proteins - metabolism / Insects / Medical research / Methicillin-Resistant Staphylococcus aureus - drug effects / Methicillin-Resistant Staphylococcus aureus - metabolism / Methicillin-Resistant Staphylococcus aureus - pathogenicity / Methicillin-Resistant Staphylococcus aureus - ultrastructure / Microbial Viability - drug effects / Morphology / Mutation / Penicillin / Penicillin-Binding Proteins - genetics / Penicillin-Binding Proteins - metabolism / Peptidoglycan - biosynthesis / Peptidoglycan Glycosyltransferase - genetics / Peptidoglycan Glycosyltransferase - metabolism / Peptidyl Transferases - genetics / Peptidyl Transferases - metabolism / Phylogeny / Proteins / Receptors, Cell Surface - genetics / Receptors, Cell Surface - metabolism / Recombinant Proteins - metabolism / Staphylococcal Infections - drug therapy / Staphylococcal Infections - metabolism / Staphylococcal Infections - microbiology / Staphylococcus infections / Synthetic biology / Virulence - drug effects