Abstract
BackgroundEcs is an ATP-binding cassette (ABC) transporter present in aerobic and facultative anaerobic Gram-positive Firmicutes. Inactivation of Bacillus subtilis Ecs causes pleiotropic changes in the bacterial phenotype including inhibition of intramembrane proteolysis. The molecule(s) transported by Ecs is (are) still unknown.Methodology/Principal FindingsIn this study we mutated the ecsAB operon in two Staphylococcus aureus strains, Newman and LS-1. Phenotypic and functional characterization of these Ecs deficient mutants revealed a defect in growth, increased autolysis and lysostaphin sensitivity, altered composition of cell wall proteins including the precursor form of staphylokinase and an altered bacterial surface texture. DNA microarray analysis indicated that the Ecs deficiency changed expression of the virulence factor regulator protein Rot accompanied by differential expression of membrane transport proteins, particularly ABC transporters and phosphate-specific transport systems, protein A, adhesins and capsular polysaccharide biosynthesis proteins. Virulence of the ecs mutants was studied in a mouse model of hematogenous S. aureus infection. Mice inoculated with the ecs mutant strains developed markedly milder infections than those inoculated with the wild-type strains and had consequently lower mortality, less weight loss, milder arthritis and decreased persistence of staphylococci in the kidneys. The ecs mutants had higher susceptibility to ribosomal antibiotics and plant alkaloids chelerythrine and sanguinarine.Conclusions/SignificanceOur results show that Ecs is essential for staphylococcal virulence and antimicrobial resistance probably since the transport function of Ecs is essential for the normal structure and function of the cell wall. Thus targeting Ecs may be a new approach in combating staphylococcal infection.
Highlights
The increased bacterial resistance to most or even all current antibiotics is a threat that necessitates development of new molecules with novel targets and/or modes of action [1]
Conclusions/Significance: Our results show that Ecs is essential for staphylococcal virulence and antimicrobial resistance probably since the transport function of Ecs is essential for the normal structure and function of the cell wall
In order to study the functional role of the Ecs ATP-binding cassette (ABC) transporter in S. aureus, we constructed two null mutations of the ecsAB operon, one which deleted large parts of both ecsA and ecsB genes (DecsAB) and another one which inserted about a 0.9 kb TargeTron intron fragment into ecsA
Summary
The increased bacterial resistance to most or even all current antibiotics is a threat that necessitates development of new molecules with novel targets and/or modes of action [1]. Bacterial ATP-binding cassette (ABC) transporters are involved in the uptake or secretion of a large variety of different biomolecules, nutrients, antimicrobial agents or ions across the cytoplasmic membrane. Some of these transporters are involved in virulence and may represent appropriate antimicrobial targets [2] as exemplified by the iron uptake systems [3,4,5]. The ecsA and ecsB genes encode the homodimeric ATP-binding and permease domains of Ecs, respectively It is still unknown which molecule(s) Ecs transport(s) and whether it functions as an exporter or an importer. The mutant phenotype clarifies the functional role of Ecs in S. aureus and other gram-positive bacteria as well as the potentiality as a novel target for antimicrobial drug development
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