Abstract
ABSTRACTTuberculosis (TB), caused by the intracellular pathogen Mycobacterium tuberculosis, remains one of the leading causes of mortality across the world. There is an urgent requirement to build a robust arsenal of effective antimicrobials, targeting novel molecular mechanisms to overcome the challenges posed by the increase of antibiotic resistance in TB. Mycobacterium tuberculosis has a unique cell envelope structure and composition, containing a peptidoglycan layer that is essential for maintaining cellular integrity and for virulence. The enzymes involved in the biosynthesis, degradation, remodelling and recycling of peptidoglycan have resurfaced as attractive targets for anti-infective drug discovery. Here, we review the importance of peptidoglycan, including the structure, function and regulation of key enzymes involved in its metabolism. We also discuss known inhibitors of ATP-dependent Mur ligases, and discuss the potential for the development of pan-enzyme inhibitors targeting multiple Mur ligases.
Highlights
Tuberculosis (TB) is a leading cause of mortality in the world today and is caused by the bacterial pathogen Mycobacterium tuberculosis
The success of M. tuberculosis as a pathogen and its innate resistance to many antimicrobial drugs can be attributed in part to its unique cell wall structure, which has low permeability for many drugs and possesses a large number of efflux pumps (Jarlier and Nikaido 1994, Brennan and Nikaido 1995)
The mycobacterial Mur ligases catalyse amide bond formation via a similar reaction mechanism to that seen in the E. coli enzymes, i.e. the formation of an activated acylphosphate derivative of UDP-MurNAc followed by a nucleophilic attack by the amino group of the amino acid or dipeptide, resulting in the formation of a peptide bond and release of inorganic phosphate (Anderson et al 1996; Falk et al 1996; Liger et al 1996; Tanner et al 1996; Vaganay et al 1996; Bertrand et al 1999) (Fig. 3E)
Summary
Tuberculosis (TB) is a leading cause of mortality in the world today and is caused by the bacterial pathogen Mycobacterium tuberculosis. Despite innovations in diagnostics and improved access to health care, the global burden of TB remains substantial with around 10 million new cases of infection and 1.6 million deaths reported due to TB in 2017 alone (WHO 2018). An estimated 457 000 cases reported in 2017 presently harbour multidrug resistant TB (MDR-TB), 8.5% of which are expected to be Received: 7 March 2019; Accepted: 7 June 2019 C FEMS 2019.
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