Peptidoglycan release and recycling in pathogenic mycobacteria.

点击翻译按钮获取中文摘要

The UN and WHO have both recognised tuberculosis (TB) as a major driver of poverty with drug-resistant forms of the disease causing high mortality rates. Drug-resistant strains have poor treatment options, and TB infection is compounded by frequent co-infection with HIV. These factors contributed to TB killing approximately 1.8 million people last year. Despite global efforts, this problem is only getting worse. The percentage of TB cases reported to be resistant to rifampicin, a front-line antibiotic rose from 31% in 2015 to 41% in 2016. This is an antibiotic resistance crisis and new therapeutic options are urgently needed. One of the most efficient ways to address this crisis is to rehabilitate existing medicines. For years beta-lactam antibiotics have not been used in TB treatment due to its endogenous broad-spectrum beta-lactamase. Recent studies, including a clinical trial have changed this view. When combined with a beta-lactamase inhibitor, beta-lactam antibiotics perform as well as existing therapeutics. Despite this, we know relatively little about the metabolism of their either eventual target, peptidoglycan in Mycobacterium tuberculosis, or how M. tuberculosis uses PG to modulate the host immune system. M. tuberculosis is the causative agent of the TB and generates one of the most complex cell walls amongst bacteria. The mycobacterial cell wall is comprised of three main layers including peptidoglycan, arabinogalactan and mycolic acids. A complex cell wall creates constraints on growth and division, which must be overcome through careful remodelling of the cell wall during division or the insertion of envelope spanning structures. This process necessarily leads to the production of small molecule metabolites, which are known to be recognised by the immune system. Peptidoglycan is a combination of long polysaccharides with a repeating disaccharide unit cross-linked through short peptides. This mesh-like structure gives the organism shape and protects it from numerous stresses. During my BBSRC Future Leader Fellowship, I have shown that mycobacteria generate two distinct forms of peptidoglycan fragments during growth as a consequence of a novel peptidoglycan recycling system. Immunostimulatory disaccharide-peptide conjugates activate host NOD receptors, while disaccharides stripped of their stem peptide serve as signals to the bacterium itself driving growth and antibiotic resistance.Peptidoglycan metabolism can be thought of as a cycle, with synthesis, remodelling, degradation and recycling intimately associated. In this BBSRC David Phillips Fellowship I will genetically and biochemically dissect these pathways using a multi-disciplinary approach. By employing unbiased genetic screens and our body's ability to sense peptidoglycan fragments I will uncover for the first time the genetic and mechanistic basis of peptidoglycan stem-peptide recycling in pathogenic mycobacteria. I will go on to dissect the molecular basis of peptidoglycan biosynthesis, remodelling and degradation so that we might better understand this important and druggable pathway in mycobacteria, with the long-term aim of reducing the burden of antimicrobial resistance.