Morphological Plasticity in Mycobacteria
Contributed by Ms. Carolyn Mulu Wu, a PhD student in A/Prof. Thomas Dick's lab who leads the mycobacterial plasticity project.
Mycobacteria are typically described as non-differentiating aerobic bacilli — rod-shaped, oxygen-dependent and lacking specialised resting cells. Even so, they can survive shock starvation in phosphate buffered saline (the 'Loebel model'), persisting in a nonreplicating state without any clear morphological change.
SPRINT-TB Theme 1 researchers took a fresh look at this adaptation. Rather than shock-starving the bacilli in saline, they added traces of a carbon source to the saline and tracked the bacterial response. Notably, giving M. smegmatis traces of a carbon source in saline (instead of shock starvation) produced a small-cell morphotype: reductive cell division yielded very short rod-shaped cells with better long-term viability. Once rich medium was supplied, these small resting cells reverted to larger standard cells before the usual division cycle resumed. The fact that a slight shift in culture conditions so readily produces a new morphotype supports the view that mycobacteria are surprisingly morphologically plastic.
The work was reported in Future Microbiology in April 2015 (Wu ML, Dick T. Metabolic flexibility and morphological plasticity in mycobacteria. Future Microbiol. 2015 Apr;10:449-52).
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Mechanism of Action of Perchlozone Solved
Contributed by Ms. Pooja Gopal, a PhD student in A/Prof. Thomas Dick's lab who leads the perchlozone project.
Perchlozone®, a new thiosemicarbazone-class drug, was approved in Russia in 2012 for multidrug-resistant tuberculosis (MDR-TB), yet its mechanism of action remained unknown. A related thiosemicarbazone, thiacetazone, is a well-studied older TB drug that inhibits the FASII dehydratase complex HadABC, part of cell wall biosynthesis in Mycobacterium tuberculosis. Thiosemicarbazone is a prodrug that must first be activated by the monooxygenase EthA.
SPRINT-TB Theme 1 ran a comparative in vitro analysis of the two drugs. Both compounds displayed an identical spectrum of activity, and spontaneous drug-resistant mutants showed cross-resistance mapping to HadABC and EthA — indicating that perchlozone, like thiacetazone, is activated by EthA and acts mainly on HadABC.
The study appeared in the International Journal of Antimicrobial Agents in April 2015 (Gopal P, Dick T. The new tuberculosis drug Perchlozone shows cross-resistance with Thiacetazone. Int J Antimicrob Agents. 2015 Apr;45(4):430-3).
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Both April 2015 reports come from SPRINT-TB Theme 1, which focuses on target discovery in Mycobacterium tuberculosis. Together they show how small adjustments to laboratory conditions can reveal new bacterial behaviours, and how comparing a newer drug with a well-characterised one can clarify how it works. Browse the archive links above to read earlier and later project updates.