Transcriptional regulation and drug resistance in Mycobacterium tuberculosis

Abstract

Bacterial drug resistance is one of the major challenges to present and future human health, as the continuous selection of multidrug resistant bacteria poses at serious risk the possibility to treat infectious diseases in the near future. One of the infection at higher risk to become incurable is tuberculosis, due to the few drugs available in the market against Mycobacterium tuberculosis. Drug resistance in this species is usually due to point mutations in the drug target or in proteins required to activate prodrugs. However, another interesting and underexplored aspect of bacterial physiology with important impact on drug susceptibility is represented by the changes in transcriptional regulation following drug exposure. The main regulators involved in this phenomenon in M. tuberculosis are the sigma factors, and regulators belonging to the WhiB, GntR, XRE, Mar and TetR families. Better understanding the impact of these regulators in survival to drug treatment might contribute to identify new drug targets and/or to design new strategies of intervention.

A marine sponge-associated mycobacterium closely related toMycobacterium tuberculosis

“…Other conserved pathogenic factors include the ESX secretion systems and a range of key mycobacterial lipid species (both discussed in detail below). Conserved regulatory systems include the PhoPR virulence regulatory system (33, 34) and several TetR-family regulators involved in M. tuberculosis antibiotic resistance such as EthR (and the associated monooxygenase EthA linked to ethionamide resistance), InhR (isoniazid) and EtbR (isoniazid and ethambutol) (35).…”

Kanamycin and Ofloxacin Activate the Intrinsic Resistance to Multiple Antibiotics in Mycobacterium smegmatis

“…The known transcriptional regulators as whiB7 , tetR , araC , lfrR , ltmA , marR , mtrA , napM , rbpA of various chemical classes, whose participation in the formation of resistance to antibiotics has been shown, were chosen for the study as we aimed to identify the transcriptional regulators, triggering the induction of resistance in the cell at maximum non-inhibiting concentrations. Their regulated genes underlying many events, such as antibiotics production, osmotic stress, efflux pumps, multidrug resistance, metabolic modulation, and pathogenesis [ 32 , 33 ]. Thus, we selected global multidrug regulators with partially unknown functions that participate in the “transcriptional drug response” ( Table 3 ).…”

“…However, we did not find a significant increase in whib7 gene expression upon streptomycin induction. This shows a potentially specific WhiB7 response to antibiotics [ 32 ].…”

“…In addition to an increase in the expression of a number of genes, we showed a decrease in the expression activity of genes upon induction with ofloxacin ( Table 3 ). Thus, we found that there is a decrease in the expression of the repressor protein genes TetR, MarR, and MtrA [ 32 , 49 ]. An interesting fact was that a decrease in the level of expression of the araC , which is a transcriptional activator of cellular transporters and removes antibiotics from the cell, was observed [ 33 ].…”

Multidimensional Applications and Challenges of Riboswitches in Biosensing and Biotherapy

“…Targeted transcription regulation is one example, [ 228 ] while another is the use of riboswitches. [ 229 ] Because of their high affinity, specificity, and widespread distribution in bacteria riboswitches can bind to specific metabolites, regulating the gene expression of metabolic pathways that are vital for bacterial growth. This makes them a potential new target for antibacterial medications ( Figure A).…”