This month, we are pleased to feature Dr. Alexandre Gouzy, Assistant Professor of Microbiology and Immunology at Weill Cornell Medicine, whose research focuses on antibiotic resistance in tuberculosis. He is one of the first awardees of our Developmental Project Award.
Pyrazinamide (PZA) is one of the four antibiotics used to treat TB, and it plays a pivotal role: adding it to the standard regimen shortened treatment from nine months to six. PZA is especially valued for killing Mycobacterium tuberculosis in difficult-to-reach necrotic lesions where other drugs struggle. But resistance is a rising concern, arising in an estimated 3 to 42% of cases depending on the region of the world and most often caused by mutations in a bacterial gene called pncA (≥70%). Detecting this resistance is notoriously hard — the mutations in pncA are highly diverse, and PZA performs poorly in standard laboratory tests, so most clinical labs cannot reliably screen for it. As a result, PZA-resistant TB often goes undetected, reducing patient survival and hampering global efforts to monitor resistance.
With support from the NYC TRAC Developmental Project Award, Dr. Gouzy's project — "Reliable Phenotypic Detection of Pyrazinamide-Resistant Tuberculosis" — tackles this gap using a lipid-rich and acidic growth medium called High-BSA-Oleate or HBO medium, in which PZA is highly active against Mtb. His goal is to reliably identify PZA-resistant clinical strains and link their resistance to specific pncA mutations, improving how resistance can be predicted from genomic data.
The project is already producing results. Dr. Gouzy and collaborators has captured PZA resistance in clinical strains for the first time using this approach, confirmed its reproducibility, and shown that some mutations in pncA, and not others, cause PZA resistance. In collaboration with the Rhee lab (WCM) and the Rock lab (Rockefeller University), Dr. Gouzy also recently discovered a new gene, rv2571c, for which loss of function mutations confer PZA resistance and which likely contributes to the 30% of PZA-R strains carrying a wild-type pncA gene.
The award has also opened new doors. Through the TRAC committee, Dr. Gouzy connected with Dr. Vincent Escuyer, who leads the mycobacteriology laboratory at the New York State Department of Health. Building on his TRAC findings, Dr. Gouzy will draw on the extensive collection of TB strains banked at the New York State laboratory to validate the HBO medium at a much larger scale. The expanded project will also seek to identify the mutations — beyond pncA and rv2571c — and bacterial lineages that drive PZA resistance, advancing the HBO medium as a practical tool for detecting PZA resistant.
