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Characterization of bacterial responses to cell-wall specific antibiotic attack

Research Groupings: Structural and molecular cell biology | Functional genomics, systems biology and genetic medicine

The bacterial cell envelope is crucial in providing a physical barrier between the cell and its environment, and giving cells their shape. The ability of bacteria to adapt and respond to changes in their cell envelope is therefore essential for survival.

A model illustrating how bacteria sense and respond to extracellular antibiotics that target the cell wall. See larger image.

We are developing Streptomyces as a model to understand how changes in the bacterial cell envelope induced by antibiotic attack are communicated to the chromosome and transduced into appropriate gene expression, thereby triggering adaptive responses (1). Antibiotics that target the bacterial cell envelope are clinically important in treatment of infectious diseases, but many inducible resistance systems in pathogens have evolved that reduce their effectiveness. The current problem with vancomycin-resistant MRSA in hospital-acquired infection is an excellent example of this.

Streptomyces species are the source of 70% of known antibiotics and they live in the soil where they encounter antibiotics produced by competing microbes, including other actinomycetes. Therefore they are the ultimate source of most antibiotic resistance genes, and likely to possess many potential genes which sense and respond to extracellular antibiotics. For example, non phathogen, non-glycopeptide producer Streptomyces coelicolor unexpectedly possesses a cluster of 7 genes which confer inducible, high-level resistance to vancomycin and even possesses novel features including two genes not present in other resistance clusters (2, 3, 4).

Images of Streptomyces coelicolor

We are initially focusing on the identification of genes expressed in response to cell wall defects caused by a range of antibacterial agents that target the cell using microarray analysis. Identified genes will then be further characterized to define their precise role in cell envelope structure and, subsequently, the mechanism by which the signal is sensed and communicated to the chromosome will be determined.This work has direct implications for medicine and for pharmaceutical companies, contributing both to their efforts to understand the molecular basis of defensive responses and resistance to antibiotics in bacteria. Also, the outputs of this work will evaluated for the development of screens for novel antibiotics that are active against bacterial cell wall biosynthesis.

Lab members
Gabriela Novotna, Adam Lucy

References