Antibiotic resistance mechanisms in M. tuberculosis: an update

Abstract

Treatment of tuberculosis (TB) has been a therapeutic challenge because of not only the naturally high resistance level of Mycobacterium tuberculosis to antibiotics but also the newly acquired mutations that confer further resistance. Currently standardized regimens require patients to daily ingest up to four drugs under direct observation of a healthcare worker for a period of 6-9 months. Although they are quite effective in treating drug susceptible TB, these lengthy treatments often lead to patient non-adherence, which catalyzes for the emergence of M. tuberculosis strains that are increasingly resistant to the few available anti-TB drugs. The rapid evolution of M. tuberculosis, from mono-drug-resistant to multiple drug-resistant, extensively drug-resistant and most recently totally drug-resistant strains, is threatening to make TB once again an untreatable disease if new therapeutic options do not soon become available. Here, I discuss the molecular mechanisms by which M. tuberculosis confers its profound resistance to antibiotics. This knowledge may help in developing novel strategies for weakening drug resistance, thus enhancing the potency of available antibiotics against both drug susceptible and resistant M. tuberculosis strains.

Keywords: Antibiotic; Bactericidal; Drug resistance; Mechanism; Mycobacterium; Tuberculosis.

Fig. 1

Possible correlation among TCA cycle, cellular redox balance and the bactericidal activity of antibiotics in M. tuberculosis. Interactions of bactericidal antibiotics with their targets trigger the oxidation of NADH, which is produced by the TCA cycle, through the electron transport chain. This results in an increased production of superoxide that destroys iron–sulfur clusters, thus releasing iron for the oxidation of the Fenton reaction. The Fenton reaction produces hydroxyl radicals that damage nucleic acids, proteins and lipid, leading to cell death. However, if these hydroxyl radicals fail to kill a bacterial cell, they may promote mutagenesis converting the cell to a drug-resistant mutant. Similarly, the anti-TB drugs isoniazid (INH) and ethionamide (ETH) kill mycobacteria by converting to free radicals, which may thus contribute to the formation of MDR M. tuberculosis strains. MD malate dehydrogenase, ICD isocitrate dehydrogenase. Redrawn with modifications from (Kohanski et al. 2007) with permission

Fig. 2

Activation of p-aminosalicylic acid (PAS) and its inhibition of the folate pathway. a Analogous structures of p-aminobenzoic acid (pABA), salicylic acid, sulfonamides and p-aminosalicylic acid (PAS) illustrated from left to right, respectively. Chemical groups highlighted in blue and red indicate variations among the chemicals. b Conversion of pABA (left, yellow) and PAS (right, green) using the same enzymes of the de novo folate synthesis, in which DHPS and DHFR are targets of sulfonamides and trimethoprim, respectively. The activated form of PAS, hydroxy-dihydrofolate that is produced following the two chemical conversions catalyzed by DHPS and DHFS adding the pteridine and glutamate groups, respectively, is proposed to inhibit the reduction of dihydrofolate to tetrahydrofolate catalyzed by DHFR activity. Alternatively, hydroxy-dihydrofolate can be further converted to hydroxy-tetrahydrofolate by DHFR and even further to other folate species carrying one-carbon groups at position N⁵ and/or N¹⁰, by enzymes of the one-carbon metabolic network. One or more of these hydroxyfolate forms may then interfere with this very pathway causing growth arrest or even death, for example, through inducing thymineless death. DHPS dihydropteroate synthase, DHFS dihydrofolate synthase, DHFR dihydrofolate reductase (color figure online)

Fig. 3

Interaction of pyrazinamide (PZA) -derived pyrazinoic acid (POA) with the RpsA protein involved in trans-translation. a Electrostatic surface potentials of the C-terminal domain of M. tuberculosis RpsA (MtRpsA^CTD, top) and its ΔA438 mutant ( ${\text{MtRpsA}}_{\mathrm{\Delta }\mathrm{A}438}^{\text{CTD}}$, bottom) around the POA-binding site. The area of prominent change is boxed. b Structural and molecular nature of RpsA^CTD–POA interactions. Electrostatic potential surface representation of the MtRpsA^CTD–POA complex (left) and a close-up view of the ligand-binding site (right). A color-code bar shows an electrostatic scale from −77 to +77 eV. c Trans-translation provides bacteria with quality control over the translation process, through rescuing stalled ribosomes and cleaning up the incomplete polypeptides. The Alanyl-tmRNA/SmpB/EF-Tu complex first recognizes stalled ribosomes at the 3′-end of an mRNA. Translation is then resumed using tmRNA as a message, thereby adding a tmRNA-encoded peptide tag to the C-terminus of the stalled polypeptide. The tagged protein and mRNA are later degraded by specific proteases and RNases, respectively. PZA is first converted to the active form POA by pyrazinamidase (PZase) present in the M. tuberculosis cytoplasm. POA binds to RpsA, thus interfering with the interaction between RpsA with tmRNA required for trans-translation. The inhibition of POA on trans-translation may lead to failure in rescuing stalled ribosome thus depleting the ribosome pool, and accumulation of incomplete toxic proteins, causing cell death following stresses. Images are reproduced from (Shi et al. 2011) and (Yang et al. 2015) with permission (color figure online)