Insights into Novel Drug Targets in Mycobacterium tuberculosis: Where Do We Stand and Where Do We Go from Here?

Safaa Kishk,Ismail Salama,Mohamed S Gomaa,Mohamed A Helal,Samia Moustafa,Claire Simons

doi:10.21608/rpbs.2018.3874.1004

Abstract

Tuberculosis (TB) is the ninth leading cause of death worldwide and the leading cause from a single infectious agent, ranking above HIV/AIDS with 6.3 million new cases of TB reported in 2016. TB is an air-borne disease associated with the aerobic bacterium Mycobacterium tuberculosis (Mtb), which mainly infects the lungs. Aerosolization of diseased pulmonary secretions, by coughing, sneezing and speaking, discharge the Mtb bacilli into the atmosphere. Infected aerosol droplet nuclei sized 1-10 μm are largely trapped in the upper nasal passages or are expelled into the pharynx by the mucociliary mechanism of the lower respiratory tract and are harmlessly swallowed and digested. Infected persons may overcome the initial TB infection, resulting in the development of asymptomatic latent TB. About 10% of individuals may develop the active disease after infection; where the bacteria undergo more rapid growth and overcome the host immune system. In cases of multi-drug resistant (MDR) strains, and extreme drug-resistant (XDR) strains, treatment fails, and the bacteria propagate and attack the host, leading to death from systemic infection. Due to the increased spread of TB worldwide, both the academic and industrial communities have initiated intensive research to develop new therapeutics targeting new enzymes such as cytochrome P450s in Mtb.

Highlights

Mycobacterium tuberculosis (Mtb) belongs to the Mycobacterium genus, characterised by its ability to synthesise mycolic acids as constituents of its cell wall. This unique envelope surrounds these bacteria, and is composed of an inner cytoplasmic membrane, an intermediate cell wall with a mixture of sugar molecules, and an exterior wall containing mycolic acid-based lipids, as well as surface signalling and transmembrane proteins. The presence of this cell wall in mycobacteria aids in the resistance of Mtb to external stresses such as macrophage environments and anti-TB drugs (Figure 1) (Bhamidi et al, 2008)
The outer membrane is comprised of 40% mycolic acids, covalently linked to arabinose and galactose subunits called arabinogalactans that are themselves linked to the peptidoglycan middle layer (Brennan et al, 1995)
The complex binds covalently to the NAD(H) recognition site of the gene encoded NADHdependent enoyl-(acyl carrier protein) reductase. This enzyme is involved in the biosynthetic pathway of mycolic acids, and isoniazid inhibits mycolic acid synthesis, which is a critical component of the Mtb cell wall (Scior et al, 2002)