Genome-wide dynamics of a bacterial response to antibiotics that target the cell envelope

Abstract

BackgroundA decline in the discovery of new antibacterial drugs, coupled with a persistent rise in the occurrence of drug-resistant bacteria, has highlighted antibiotics as a diminishing resource. The future development of new drugs with novel antibacterial activities requires a detailed understanding of adaptive responses to existing compounds. This study uses Streptomyces coelicolor A3(2) as a model system to determine the genome-wide transcriptional response following exposure to three antibiotics (vancomycin, moenomycin A and bacitracin) that target distinct stages of cell wall biosynthesis.ResultsA generalised response to all three antibiotics was identified which involves activation of transcription of the cell envelope stress sigma factor σE, together with elements of the stringent response, and of the heat, osmotic and oxidative stress regulons. Attenuation of this system by deletion of genes encoding the osmotic stress sigma factor σB or the ppGpp synthetase RelA reduced resistance to both vancomycin and bacitracin. Many antibiotic-specific transcriptional changes were identified, representing cellular processes potentially important for tolerance to each antibiotic. Sensitivity studies using mutants constructed on the basis of the transcriptome profiling confirmed a role for several such genes in antibiotic resistance, validating the usefulness of the approach.ConclusionsAntibiotic inhibition of bacterial cell wall biosynthesis induces both common and compound-specific transcriptional responses. Both can be exploited to increase antibiotic susceptibility. Regulatory networks known to govern responses to environmental and nutritional stresses are also at the core of the common antibiotic response, and likely help cells survive until any specific resistance mechanisms are fully functional.

In Vivo Studies Suggest that Induction of VanS-Dependent Vancomycin Resistance Requires Binding of the Drug to d -Ala- d -Ala Termini in the Peptidoglycan Cell Wall

“…In addition, D-Ala-D-Lac-containing cell wall precursors are unlikely to be the optimal substrates for all of the housekeeping enzymes involved in peptidoglycan biosynthesis and cell wall homeostasis. Hesketh et al (32) showed that vancomycin treatment significantly altered the expression of five genes encoding penicillin-binding proteins (PBPs) in S. coelicolor, suggesting that a different spectrum of enzymes may be required to handle the changes induced in cell wall precursor substrate biosynthesis. For all of these reasons, synthesizing the minimal amount of D-Ala-D-Lac-containing PG precursors required for survival under the prevailing vancomycin concentration would be advantageous.…”

“…All determinations were performed in triplicate, and the results were analyzed using 7300 System SDS software (version 1.4; Applied Biosystems). Results were normalized to an endogenous control gene, SCO4742, selected from previous microarray data as being constantly and constitutively expressed under the conditions used (31,32).…”

Comparative Metabolic Systems Analysis of Pathogenic Burkholderia

“…Ectoine production has been shown to be upregulated under stress conditions and, interestingly, in mutant strains of soil bacteria that are resistant to antibiotics targeting the cell envelope (e.g., Streptomyces coelicolor) and protein synthesis (e.g., Nocardiopsis sp. strain FU40) (50,51). These studies theorize that ectoine upregulation may be part of a broad secondary metabolism response to changes in regulation due to resistance-related mutations.…”

Socially mediated induction and suppression of antibiosis during bacterial coexistence

“…Equally, we predict that social growth will elicit defensive strategies to suppress or attenuate antibiotic production in competitors (18). Though this study was not aimed at identifying the mechanisms of elicitation and attenuation, both outcomes have been observed and can result from diverse mechanisms, including a response to stress caused by resource competition or antibiotic exposure (7,(24)(25)(26), or via enzymatic degradation of antibiotics or the signals regulating their production (2). Fig.…”