A New Wrinkle in TB’s Drug Resistance

John, 3, who suffers from multi-drug-resistant tubeculosis (MDR-TB), is held by his mother Elizabeth, also an MDR-TB case, after she gave him his medication at an MSF-run clinic in Nairobi.
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John, 3, who suffers from multi-drug-resistant tubeculosis (MDR-TB), is held by his mother Elizabeth, also an MDR-TB case, after she gave him his medication at an MSF-run clinic in Nairobi. Tony Karumba/AFP/Getty Images

Mycobacterium tuberculosis’s ability to develop resistance to antibiotics has long been a threat to global health. Matthew Wipperman, PhD, MSc, a research scientist in the Immunology Program at Memorial Sloan Kettering Cancer Center, and colleagues recently published a paper in Molecular Cell that describes a new mechanism of regulation of drug resistance in bacteria.

What’s the problem?

Antibiotic drug resistance in the world’s 9th leading cause of death, tuberculosis, is solely the result of mistakes made during DNA replication or repair, rather than by swapping antibiotic resistance genes from other bacteria. Mistakes that inactivate drug targets or drug activating enzymes allow TB to resist antibiotics; however, the mechanisms that control this DNA mutagenesis are poorly defined not just in TB but in many bacteria.

What did you find?

This paper elucidates a new mechanism that controls this DNA mutagenesis in TB and other mycobacteria through the common DNA repair enzyme RecA. We found that RecA modification by phosphorylation (a reversible “decoration” to a protein that may alter how the protein works) controls its participation in mutagenesis, while preserving its other functions. We also found that a membrane lipid (called cardiolipin) also participates in controlling this mutagenesis function of RecA.

How this will make a difference?

Despite a promising pipeline, only 1 new drug has been approved for multidrug resistant TB since 1963! The number of cases of MDR-TB are rising each year, so it is critical that we prioritize the development of new antibiotics to target MDR TB. Understanding how TB becomes resistant to drugs in the first place is critical to developing and administering newer, better therapies.

 

Ed. Note: This is the first installment of Quick Study, a new occasional Q&A series in GHN highlighting newly published scientific articles of note for the global health community.

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