Tuberculosis

Could Blocking TB Bacteria Pathways Improve Treatment?

Blocking the metabolic “escape” pathways of Mycobacterium tuberculosis may reduce resistance to the bacteria and may lead to shorter treatments, according to a new study.1

Patients with tuberculosis (TB) often struggle with complying with treatment, because the slow killing of the infecting organism, through treatment, typically takes 6 months to complete. Additionally, the prolonged use of treatment can lead to drug-resistance.
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Shortening the time of treatment from could improve patient compliance and drug resistance. One way to achieve this goal may be to block TB bacteria—M tuberculosis—from shifting to another metabolic pathway.

For their study, the researchers examined how the M tuberculosis H37Rv strain prolongs survival following exposure to twice the minimal inhibitory bactericidal concentrations of 5 antimicrobials—isoniazid, rifampicin, moxifloxacin, mefloquine, and bedaquiline—for periods of 24 h, 48 h, 4 d, and 6 d. Quantitative shotgun mass spectrometry was used to assess the proteomic responses of the bacteria to the 5 compounds.

In their assessment, the researchers identified numerous sets of de novo bacterial proteins over 6-day treatment and found several shared sets of predominant proteins and enzymes that belonged simultaneously to a number of diverse pathways. Overexpression of some of these proteins in nonpathogenic Mycobacterium smegmatis prolonged bacterial survival upon exposure to bactericidal concentrations of antimicrobials.

“When we looked at the enzymes carefully, we realized the enzymes being synthesized by the bacteria were enzymes connecting several different metabolic pathways," the researchers noted. "Then we came up with the idea that maybe what the bacteria were trying to do, in the presence of a bactericidal compound that was threatening their way of living, was use other ways to survive. One of the things we saw, for example, was a shift to an anaerobic metabolism, which makes a lot of drugs inactive and incapable of killing bacteria.”2

The researchers went on to explain that inactivating the genes of some of these enzymes led to improved drug efficacy against  M tuberculosis.

“If we can use another compound that inhibits bacteria from shifting metabolic pathways, then we get a more reliable and desirable synergy of therapy. That might have a significant impact on reducing the time needed for therapy and improving compliance and, consequently, reducing the emergence of resistance,” the researchers concluded.

—Christina Vogt

References:

  1. Danelishvili L, Shulzhenko N, Chinison JJJ, et al. Mycobacterium tuberculosis proteome response to anti-tuberculosis compounds reveals metabolic “escape” pathways that prolong bacterial survival. Antimicrob Agents Chemother. 2017;61(6). doi:10.1128/AAC.00430-17.
  2. Blocking TB germs’ metabolic ‘escape pathways’ may be key to better, shorter treatment [press release]. Corvallis, OR: Oregon State University; May 30, 2017. http://oregonstate.edu/ua/ncs/archives/2017/may/blocking-tb-germs%E2%80%99-metabolic-%E2%80%98escape-pathways%E2%80%99-may-be-key-better-shorter-treatment. Accessed May 31, 2017.