The ATP-Binding Cassette (ABC) Transport Systems in Mycobacterium tuberculosis: Structure, Function, and Possible Targets for Therapeutics

Abstract

Mycobacterium tuberculosis is the etiological agent of tuberculosis (TB), a disease that affects millions of people in the world and that is associated with several human diseases. The bacillus is highly adapted to infect and survive inside the host, mainly because of its cellular envelope plasticity, which can be modulated to adapt to an unfriendly host environment; to manipulate the host immune response; and to resist therapeutic treatment, increasing in this way the drug resistance of TB. The superfamily of ATP-Binding Cassette (ABC) transporters are integral membrane proteins that include both importers and exporters. Both types share a similar structural organization, yet only importers have a periplasmic substrate-binding domain, which is essential for substrate uptake and transport. ABC transporter-type importers play an important role in the bacillus physiology through the transport of several substrates that will interfere with nutrition, pathogenesis, and virulence. Equally relevant, exporters have been involved in cell detoxification, nutrient recycling, and antibiotics and drug efflux, largely affecting the survival and development of multiple drug-resistant strains. Here, we review known ABC transporters from M. tuberculosis, with particular focus on the diversity of their structural features and relevance in infection and drug resistance.

An Epistatic Network Describes oppA and glgB as Relevant Genes for Mycobacterium tuberculosis

“…The relevance of the characterization of the peptide transporter system has been described by Dasgupta et al (2010) . Previous studies uncovered the novel observation that this peptide transporter modulates the innate immune response of macrophages infected ( Cassio Barreto de Oliveira and Balan, 2020 ) with Mtb, but the epistatic interactions of oppA with other loci remain unknown.…”

“…In addition, it has also been demonstrated that this transporter is implicated in the maintenance of chronic infection in murine models by mediating the transport of a molecule that can directly or indirectly modulate the proinflammatory host response. Despite having different structures, BacA and OppA shared their ability to transport a wide range of substrates; in particular, the shared capacity of import peptides related to the innate immune response suggests a complex regulation and interaction of these transporters, guaranteeing the need to carry out studies at the level of gene regulation and function in the near future ( Domenech et al, 2009 ; Cassio Barreto de Oliveira and Balan, 2020 ; Rempel et al, 2020 ).…”

Diverse Aquatic Animal Matrices Play a Key Role in Survival and Potential Virulence of Non-O1/O139 Vibrio cholerae Isolates

“…Deletion of this methyltransferase I resulted in the increased susceptibility of Melissococcus plutonius to mirosamicin antibiotics (Takamatsu et al, 2018 ). On the other hand, the ABC transporter substrate binding protein (Spots T388, T490, and T549) was produced by V. cholerae N4-21 when grown in P. viridis matrix, which participated in cell detoxification, antibiotic, and drug efflux in M. tuberculosis and greatly affected the survival and development of many drug-resistant strains (Cassio Barreto De Oliveira and Balan, 2020 ). Moreover, the TolC family outer membrane protein (Spots T446), produced by V. cholerae N4-21 in P. viridis matrix, was present in many pathogenic Gram-negative bacteria, including V. cholerae, E. coli , and P. aeruginosa , and formed an outer membrane channel that removed drugs and toxins from cells (Leong et al, 2014 ; Pattanayak et al, 2021 ).…”

MOLECULAR BASIS AND INTEGRATIVE ANALYSIS OF Rv1463 AS PROBABLE CONSERVED ATP-BINDING PROTEIN BY COMPUTATIONAL APPROACH

“…The process includes the binding of nuclear binding domains (NBDs) of ABC transporters with the Adenine triphosphate (ATP) and followed by ATP hydrolysis for energy production required for this process to be carried out. NBD is the most conserved domain of the transporters, having all about 40-45% conserved sequences, irrespective of their substrate specificity and their origin [12,13]. Approximately all NBD-containing proteins are responsible for the transportation of substrate across the plasma membranes.…”