Recent updates on drug resistance in Mycobacterium tuberculosis

Abstract

Summary Tuberculosis (TB) along with acquired immune deficiency syndrome and malaria rank among the top three fatal infectious diseases which pose threat to global public health, especially in middle and low income countries. TB caused by Mycobacterium tuberculosis (Mtb) is an airborne infectious disease and one‐third of the world's population gets infected with TB leading to nearly 1·6 million deaths annually. TB drugs are administered in different combinations of four first‐line drugs (rifampicin, isoniazid, pyrazinamide and ethambutol) which form the core of treatment regimens in the initial treatment phase of 6–9 months. Several reasons account for the failure of TB therapy such as (i) late diagnosis, (ii) lack of timely and proper administration of effective drugs, (iii) lower availability of less toxic, inexpensive and effective drugs, (iv) long treatment duration, (v) nonadherence to drug regimen and (vi) evolution of drug‐resistant TB strains. Drug‐resistant TB poses a significant challenge to TB therapy and control programs. In the background of worldwide emergence of 558 000 new TB cases with resistance to rifampicin in the year 2017 and of them, 82% becoming multidrug‐resistant TB (MDR‐TB), it is essential to continuously update the knowledge on the mechanisms and molecular basis for evolution of Mtb drug resistance. This narrative and traditional review summarizes the progress on the anti‐tubercular agents, their mode of action and drug resistance mechanisms in Mtb. The aim of this review is to provide recent updates on drug resistance mechanisms, newly developed/repurposed anti‐TB agents in pipeline and international recommendations to manage MDR‐TB. It is based on recent literature and WHO guidelines and aims to facilitate better understanding of drug resistance for effective TB therapy and clinical management.

Drug-Resistant Tuberculosis 2020: Where We Stand

“…It is assumed that the innermost hydrophilic layers of PG and AG hinder the penetration of hydrophobic molecules. Instead, in the external part of the envelope, the PG and AG layers are linked to the hydrophobic MA layer, formed by long-chain fatty acids that restrict the penetration of hydrophilic drugs [18,20]. In principle, more lipophilic drugs, such as rifamycins, macrolides, and some FQs, diffuse by passive transport into and through the lipid-rich cell wall [45,46].…”

“…Small hydrophilic drugs traverse the cell wall of bacteria via water-filled porins, without energy consumption. M. tuberculosis encodes at least two porin-like proteins (OmpA, encoded by Rv0899 and Rv1698), but the role of porins in Mtb drug uptake and susceptibility needs to be further investigated [18,20,50,51]. Penetration of hydrophilic β-lactam antibiotics through the mycobacterial cell was about 100 times lower than in the Escherichia coli cell wall [20].…”

“…Efflux pumps (EPs) are transmembrane proteins that provide resistance by expelling the drugs from the interior to the exterior of the cell. Five EP families are known, organized on the basis of energetic and structural characteristics: the ATP-binding cassette (ABC) superfamily, the major facilitator superfamily (MFS), the multidrug and toxic compound extrusion (MATE) family, the small multidrug resistance (SMR) family and the resistance nodulation division (RND) superfamily [18,19,46,56,57]. The ATP-energized ABC members are primary transporters, while the others are secondary transporters energized by proton gradients (MFS, SMR, RND) or sodium gradients (MATE).…”

“…Among drug inactivating enzymes, Mtb β-lactamases are less effective than those of other bacteria to hydrolyse β-lactams, but their activity, together with slow penetration across the cell wall and low affinity for penicillin-binding proteins, is good enough to render Mtb intrinsically resistant to most β-lactams [18,20]. The most important Mtb β-lactamase (BlaC) is thought to localize in the PS, and shows broad substrate specificity, including carbapenems, which are usually resistant to the β-lactamases of other bacteria.…”

“…Naturally occurring high levels of antibiotic resistance in tubercle bacilli (intrinsic resistance) [18][19][20]; 4.…”