ABSTRACT
The genus mycobacterium includes several species that are known to cause infections in humans. The microorganisms are classified into tuberculous and non-tuberculous based on their morphological characteristics, defined by the dynamic relationship between the host defenses and the infectious agent. Non-tuberculous mycobacteria (NTM) include all the species of mycobacterium other than the ones that cause tuberculosis (TB). The group of NTM contains almost 200 different species and they are found in soil, water, animals-both domestic and wild-milk and food products, and from plumbed water resources such as sewers and showerhead sprays. A systematic review of Medline between 1946 and 2014 showed an 81% decline in TB incidence rates with a simultaneous 94% increase in infections caused by NTM. Prevalence of infections due to NTM has increased relative to infections caused by TB owing to the stringent prevention and control programs in Western countries such as the USA and Canada. While the spread of typical mycobacterial infections such as TB and leprosy involves human contact, NTM seem to spread easily from the environment without the risk of acquiring from a human contact except in the case of M. abscessus in patients with cystic fibrosis, where human transmission as well as transmission through fomites and aerosols has been recorded. NTM are opportunistic in their infectious processes, making immunocompromised individuals such as those with other systemic infections such as HIV, immunodeficiencies, pulmonary disease, or usage of medications such as long-term corticosteroids/TNF-α inhibitors more susceptible. This review provides insight on pathogenesis, treatment, and BCG vaccine efficacy against M. leprae and some important NTM infections.
ABSTRACT
Twenty lupane type A-ring azepano-triterpenoids were synthesized from betulin and its related derivatives and their antitubercular activity against Mycobacterium tuberculosis, mono-resistant MTB strains, and nontuberculous strains Mycobacterium abscessus and Mycobacterium avium were investigated in the framework of AToMIc (Anti-mycobacterial Target or Mechanism Identification Contract) realized by the Division of Microbiology and Infectious Diseases, NIAID, National Institute of Health. Of all the tested triterpenoids, 17 compounds showed antitubercular activity and 6 compounds were highly active on the H37Rv wild strain (with MIC 0.5 µM for compound 7), out of which 4 derivatives also emerged as highly active compounds on the three mono-resistant MTB strains. Molecular docking corroborated with a machine learning drug-drug similarity algorithm revealed that azepano-triterpenoids have a rifampicin-like antitubercular activity, with compound 7 scoring the highest as a potential M. tuberculosis RNAP potential inhibitor. FIC testing demonstrated an additive effect of compound 7 when combined with rifampin, isoniazid and ethambutol. Most compounds were highly active against M. avium with compound 14 recording the same MIC value as the control rifampicin (0.0625 µM). The antitubercular ex vivo effectiveness of the tested compounds on THP-1 infected macrophages is correlated with their increased cell permeability. The tested triterpenoids also exhibit low cytotoxicity and do not induce antibacterial resistance in MTB strains.