Contents lists available at ScienceDirect Biomedicine & Pharmacotherapy journal homepage: www.elsevier.com/locate/biopha Review Cell wall: A versatile fountain of drug targets in Mycobacterium tuberculosis Zubair Shanib Bhat a,b, ⁎ , Muzafar Ahmad Rather a,c , Mubashir Maqbool a,d , Hafiz UL Lah e , Syed Khalid Yousuf b,e , Zahoor Ahmad a,b, ⁎ a Clinical Microbiology and PK/PD Division, Indian Institute of Integrative Medicine (IIIM), Campus, Sanat Nagar, Srinagar, Jammu & Kashmir 190005, India b Academy of Scientific and Innovative Research (AcSIR), CSIR- Indian Institute of Integrative Medicine (IIIM), Campus, Sanat Nagar, Srinagar, Jammu & Kashmir 190005, India c Department of Biochemistry, University of Kashmir, Srinagar, Jammu & Kashmir 190006, India d Department of Zoology, University of Kashmir, Srinagar, Jammu & Kashmir 190006, India e Medicinal Chemistry Division, Indian Institute of Integrative Medicine (IIIM), Campus, Sanat Nagar, Srinagar, Jammu & Kashmir 190005, India ARTICLE INFO Keywords: Mycobacterium tuberculosis Mycobacterium cell wall Cell wall inhibitors Tuberculosis drug discovery Drug targets Drug resistance ABSTRACT Tuberculosis is the leading infectious disease responsible for an estimated one and a half million human deaths each year around the globe. HIV-TB coinfection and rapid increase in the emergence of drug resistant forms of TB is a dangerous scenario. This underlines the urgent need for new drugs with novel mechanism of action. A plethora of literature exist that highlight the importance of enzymes involved in the biosynthesis of myco- bacterial cell wall responsible for its survival, growth, permeability, virulence and resistance to antibiotics. Therefore, assembly of cell wall components is an attractive target for the development of chemotherapeutics against Mycobacterium tuberculosis. The aim of this review is to highlight novel sets of enzyme inhibitors that disrupt its cell wall biosynthetic pathway. These include the currently approved first and second line drugs, candidates in clinical trials and current structure activity guided endeavors of scientific community to identify new potent inhibitors with least cytotoxicity and better efficacy against emergence of drug resistance till date. 1. Introduction Tuberculosis (TB) [1] continues to remain a major global health problem in humans and a leading cause of death worldwide killing 1.5 million each year [2,3]. It is one of the most common opportunistic infection affecting HIV-positive individuals and leading cause of death in people living with HIV (PLHIV) [4,5]. HIV modifies the clinical manifestation of TB thereby delaying its diagnosis and early treatment. Today, HIV-TB co-infection along with emergence of multidrug-re- sistant TB (MDR‐TB) poses a serious global threat. A vision of transition from stopping TB to ending TB is turning bleak. Therefore, addressing the burden of HIV-TB co-infection and optimizing current TB che- motherapy for more rapid and effective treatment of MDR-TB are major challenges. Innovation in search of new and effective anti-TB drugs (ATD’s) will play a crucial role in curbing TB more effectively [6]. Decades of research all around the globe has led to the discovery of new molecules with anti-TB potential that are being currently evaluated both in pre-clinical and clinical stages of drug development. Gene products involved in controlling vital aspects of mycobacterial structure and metabolism like cell wall biosynthesis, DNA replication, RNA synthesis, protein synthesis, energy and folate metabolism represent attractive drug targets in Mycobacterium tuberculosis. However, in the last four decades of TB drug discovery, only a handful of antibiotics against drug resistant forms of M. tuberculosis are currently im- plemented by WHO owing to its tough cell wall with least permeability. The low permeability of the cell wall appears to be vital for survival of mycobacteria within the host as mycobacterial porin proteins are in- efficient in allowing the permeation of solutes and hydrophilic anti- microbials agent across the cell wall inside the cytosol [7]. Advances in understanding the biology of mycobacterium has highlighted the im- portance of M. tuberculosis cell wall architecture, its biosynthetic pathways and permeability to play a pivotal role in the discovery of new ATD’s to curb the increasing incidence of drug resistance [8]. In this review, we have attempted to highlight the drug targets in- volved in cell wall biosynthesis, their inhibitors and current efforts of researchers in this direction to find answers to emerging drug resistance in the light of cell wall inhibition from discovery to present times. Herein, we first briefly describe the cell wall architecture of M. tu- berculosis with an aim to depict the enzymes and constituents involved in biosynthetic pathway for possible interference by antibiotics. This is followed by detailed mechanism of action of various cell wall inhibitors discovered so far that target cell wall of M. tuberculosis. These include: http://dx.doi.org/10.1016/j.biopha.2017.09.036 Received 23 July 2017; Received in revised form 7 September 2017; Accepted 10 September 2017 ⁎ Corresponding authors at: Clinical Microbiology, PK/PD Laboratory, Indian Institute of Integrative Medicine, Sanat Nagar, Srinagar 190005, India. E-mail addresses: zubairbhats@yahoo.com, zuby.biotech@gmail.com (Z.S. Bhat), zahoorap@iiim.ac.in (Z. Ahmad). Biomedicine & Pharmacotherapy 95 (2017) 1520–1534 0753-3322/ © 2017 Elsevier Masson SAS. All rights reserved. MARK