Mycobacterium tuberculosis Molecular Determinants of Infection, Survival Strategies, and Vulnerable Targets

Abstract

Mycobacterium tuberculosis is the causative agent of tuberculosis, an ancient disease which, still today, represents a major threat for the world population. Despite the advances in medicine and the development of effective antitubercular drugs, the cure of tuberculosis involves prolonged therapies which complicate the compliance and monitoring of drug administration and treatment. Moreover, the only available antitubercular vaccine fails to provide an effective shield against adult lung tuberculosis, which is the most prevalent form. Hence, there is a pressing need for effective antitubercular drugs and vaccines. This review highlights recent advances in the study of selected M. tuberculosis key molecular determinants of infection and vulnerable targets whose structures could be exploited for the development of new antitubercular agents.

Targeting Genome Integrity in Mycobacterium Tuberculosis: From Nucleotide Synthesis to DNA Replication and Repair

“…In MTB, as observed in other bacteria, the NER cascade begins with formation of a macromolecular complex between UvrA and UvrB proteins that were structurally and biochemically characterized [86,87]. It was demonstrated that the two proteins interact in solutions in the absence of ligands, supporting the hypothesis that the scouting of damaged sites inside DNA could involve pre-assembled UvrA 2 /UvrB 2 heterotetramers, and suggesting the possibility of targeting UvrA-UvrB in order to block the entire NER cascade in MTB [88,89]. Moreover, an inhibitor of the endonuclease activity of the UvrABC complex [2-(5-amino-1,3,4-thiadiazol-2-ylbenzo[f]chromen-3-one) (ATBC)] was identified, which was active at a micromolar concentration [90].…”

Blocking the Trigger: Inhibition of the Initiation of Bacterial Chromosome Replication as an Antimicrobial Strategy

“…We predict that, with continued development of in vitro and cell-based assays, and with large scale screening efforts, compounds that inhibit key aspects orisome assembly and function will be found. Further, the strategy of examining protein-protein interactions in unexploited pathways can be extended to other aspects of DNA biology, including the elongation phase of DNA replication [99,107] and DNA repair [142,143], and used to discover lead compounds to develop novel antibiotics to fight the scourge of drug-resistant bacterial infections.…”

Mycobacterium tuberculosis Uses Mce Proteins to Interfere With Host Cell Signaling

“…Inhaled aerosolized bacteria primarily encounter alveolar macrophages and their ability to persist in an antimicrobial environment is critical for establishing an infection (Simmons et al, 2018). One of the intriguing methods of survival is how the pathogen modulates host cell signaling for its own advantage (Ferraris et al, 2018). There are several examples of this strategy including PtpA binding of host ubiquitin leading to the suppression of host Jnk, p38, and NF-κB pathways (Wang et al, 2015); ESAT-6 binding to host TLR2 leading to inhibition of NF-κB activation within host cells (Pathak et al, 2007); Zmp1 prevents host phagosome maturation by inhibiting the production of IL-1β (Master et al, 2008); and lipoarabinomannan (LAM) prevents apoptosis of host cells via promoting phosphorylation of Bad in the PI-3K/Akt pathway to name a few (Maiti et al, 2001).…”