Tuberculosis, a bacterial lung infection, is one of the leading causes of death worldwide and is becoming increasingly resistant to antibacterial treatments.
Neil Osheroff, PhD, and colleagues assessed a new class of antibacterial drugs called SPTs (spiropyrimidinetriones), which target the same enzyme, gyrase, as fluoroquinolones, the most prescribed class of broad-spectrum antibacterials.
The researchers report in ACS Infectious Diseases that five novel SPTs had high activity against Mycobacterium tuberculosis gyrase and increased levels of DNA cleavage, which leads to cell death. The SPTs had similar activity to two fluoroquinolones (moxifloxacin and ciprofloxacin) and greater activity than an SPT that is in phase 3 clinical trials (zoliflodacin). They were effective against gyrase with mutations associated with fluoroquinolone resistance and had low activity against a human enzyme that is similar to gyrase, which is important for minimizing off-target effects.
The findings support the potential of novel SPTs for treating tuberculosis, especially strains that are resistant to fluoroquinolones.
Jo Ann Byl, MS, research specialist, senior, in the Department of Biochemistry at Vanderbilt University, is the first author of the paper. Byl and Osheroff, who holds the John G. Coniglio Chair in Biochemistry at Vanderbilt, collaborated with Ben Bax, PhD, at Cardiff University, and Rudolf Mueller, Gregory Basarab and Kelly Chibale, PhD, at the Drug Discovery and Development Centre at the University of Cape Town in South Africa, the only drug development center in Africa that is focused on African diseases.
The research was supported by a Veterans Administration Merit Review award, National Institutes of Health grant GM126363, Global Health Grants from the Bill and Melinda Gates Foundation, the Division of Intramural Research of the NIAID/NIH, and the Strategic Health Innovation Partnerships unit of the South African Medical Research Council.
