@article{3009d6f953f248d38137e4e336b7a075,
title = "A trimethoprim derivative impedes antibiotic resistance evolution",
abstract = "The antibiotic trimethoprim (TMP) is used to treat a variety of Escherichia coli infections, but its efficacy is limited by the rapid emergence of TMP-resistant bacteria. Previous laboratory evolution experiments have identified resistance-conferring mutations in the gene encoding the TMP target, bacterial dihydrofolate reductase (DHFR), in particular mutation L28R. Here, we show that 4{\textquoteright}-desmethyltrimethoprim (4{\textquoteright}-DTMP) inhibits both DHFR and its L28R variant, and selects against the emergence of TMP-resistant bacteria that carry the L28R mutation in laboratory experiments. Furthermore, antibiotic-sensitive E. coli populations acquire antibiotic resistance at a substantially slower rate when grown in the presence of 4{\textquoteright}-DTMP than in the presence of TMP. We find that 4{\textquoteright}-DTMP impedes evolution of resistance by selecting against resistant genotypes with the L28R mutation and diverting genetic trajectories to other resistance-conferring DHFR mutations with catalytic deficiencies. Our results demonstrate how a detailed characterization of resistance-conferring mutations in a target enzyme can help identify potential drugs against antibiotic-resistant bacteria, which may ultimately increase long-term efficacy of antimicrobial therapies by modulating evolutionary trajectories that lead to resistance.",
author = "Manna, {Madhu Sudan} and Tamer, {Yusuf Talha} and Ilona Gaszek and Nicole Poulides and Ayesha Ahmed and Xiaoyu Wang and Toprak, {Furkan C.R.} and Woodard, {Da Nae R.} and Koh, {Andrew Y.} and Williams, {Noelle S.} and Dominika Borek and Atilgan, {Ali Rana} and Hulleman, {John D.} and Canan Atilgan and Uttam Tambar and Erdal Toprak",
note = "Funding Information: We thank all the members of Toprak lab and Tambar lab for their help. We acknowledge Ahmed C. Toprak for his help to purify the clinical isolate of E. coli strain. Thanks to Priyanjana Mitra for her help with morbidostat experiments. We acknowledge Michael Farid and Nihal Ezgi Temamogullari Wood for their help with MatLab codes. We thank Marinelle Rodrigues for the helpful discussion during manuscript preparation. This work was supported by the UTSW Endowed Scholars Program (E.T., U.T.), Human Frontiers Science Program Research grant RGP0042/2013 (E.T.), National Institutes of Health grant R01GM125748 (E.T.) and R21GM126406 (D.B.), The National Institute of General Medical Sciences (D.B.), Welch Foundation I-1748 (U.T.), a Career Development Award from Research to Prevent Blindness (J.H.), as well as the Roger and Dorothy Hirl Research Fund (J.D.H.). D.B. is a co-founder of Ligo Analytics. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2021",
month = dec,
doi = "10.1038/s41467-021-23191-z",
language = "English (US)",
volume = "12",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}