Immunobiology of tubercle bacilli and prospects of immunomodulatory drugs to tackle tuberculosis (TB) and other non-tubercular mycobacterial infections

Abstract

The COVID-19 pandemic has set back progress made on antimicrobial resistance (AMR). Without urgent re-focus, we risk slowing down drug discovery and providing treatment for drug resistant Mycobacterium tuberculosis. Unique in its immune evasion, dormancy and resuscitation, the causal pathogens of tuberculosis (TB) have demonstrated resistance to antibiotics with efflux pumps and the ability to form biofilms. Repurposing drugs is a prospective avenue for finding new anti-TB drugs. There are many advantages to discovering novel targets of an existing drug, as the pharmacokinetic and pharmacodynamic properties have already been established, they are cost-efficient and can be commercially accelerated for the new development. One such group of drugs are non-steroidal anti-inflammatory drugs (NSAIDs) that are originally known for their ability to supress the host proinflammatory responses. In addition to their anti-inflammatory properties, some NSAIDs have been discovered to have antimicrobial modes of action. Of particular interest is Carprofen, identified to inhibit the efflux mechanism and disrupt biofilm formation in mycobacteria. Due to the complexities of host-pathogens interactions in the lung microbiome, inflammatory responses must carefully be controlled alongside the in vivo actions of the prospective anti-infectives. This critical review explores the potential dual role of a selection of NSAIDs, as an anti-inflammatory and anti-tubercular adjunct to reverse the tide of antimicrobial resistance in existing treatments.

Keywords: Antimicrobial resistance (AMR); Carprofen; Drug repurposing; Mycobacterium tuberculosis (Mtb); NSAIDs; Non-tubercular mycobacteria (NTM); Tuberculosis.

Fig. 1

Selected carbazole structures. A) carbazole scaffold composed of two benzene rings with a pyrrole ring in the centre; B) Carprofen, commonly used in veterinary treatment - PubChem CID, 2581 (National Centre for Biotechnology Information, 2022a); C) Carvedilol (S-isomer), a nonselective beta-adrenergic blocker used to treat cardiac disease in humans PubChem CID, 2585 (National Centre for Biotechnology Information, 2022b); D) Frovatriptan, a serotonin 1d receptor agonist – PubChem CID, 77992 (National Centre for Biotechnology Information, 2022c).

Fig. 2

NSAIDs such as Carprofen (including the carbazole scaffold in the centre) demonstrating both anti-infective and anti-inflammatory properties. A) Cyclooxygenase inhibition in eukaryotes (Chandrasekharan and Simmons, 2004); B) mediation of non-productive inflammation in the lungs (Ravimohan et al., 2018, Malherbe et al., 2016); C) RHO-GTPase is a target of NSAIDs in eukaryotes, the homologue in M. tuberculosis is Translation initiation factor 2 protein, InfB (Rv2839c) in prokaryotes (Guzman et al., 2013); D) membrane potential disruption (Maitra et al., 2020); E) Efflux pump inhibition (Maitra et al., 2020); F) sliding clamp inhibition in E. coli (adapted from Yin et al., 2014); G) biofilm inhibition (Maitra et al., 2020).