Cerastecin Inhibition of the Lipooligosaccharide Transporter MsbA to Combat <i>Acinetobacter baumannii</i>: From Screening Impurity to <i>In Vivo</i> Efficacy
<i>Acinetobacter baumannii</i>, a commonly multidrug-resistant Gram-negative bacterium responsible for large numbers of bloodstream and lung infections worldwide, is increasingly difficult to treat and constitutes a growing threat to human health. Structurally novel antibacterial chemical matter that can evade existing resistance mechanisms is essential for addressing this critical medical need. Herein, we describe our efforts to inhibit the essential <i>A. baumannii</i> lipooligosaccharide (LOS) ATP-binding cassette (ABC) transporter MsbA. An unexpected impurity from a phenotypic screening was optimized as a series of dimeric compounds, culminating with <b>1</b> (cerastecin D), which exhibited antibacterial activity in the presence of human serum and a pharmacokinetic profile sufficient to achieve efficacy against <i>A. baumannii</i> in murine septicemia and lung infection models.
Authors
- Rodger Tracy
- James Mulhearn (ORCID: https://orcid.org/0009-0002-0846-112X)
- Ronald E. Painter
- Michelle F. Homsher
- Izzat T. Raheem (ORCID: https://orcid.org/0000-0002-6769-8816)
- Michael Hennig (ORCID: https://orcid.org/0000-0002-1839-2351)
- Edward DiNunzio
- Terri Kelly
- Andrii Ishchenko (ORCID: https://orcid.org/0000-0002-3797-0604)
- Ashley B. Nomland
- Sarah W. Li
- Carolyn Bahnck-Teets
- Matthieu Jouffroy (ORCID: https://orcid.org/0000-0003-4478-2502)
- Carl J. Balibar (ORCID: https://orcid.org/0000-0003-0854-4224)
- Alan Hruza
- S.M. Soisson (ORCID: https://orcid.org/0000-0002-5089-3885)
- Tamara D. Cabalu
- Zhe Wu (ORCID: https://orcid.org/0000-0003-4210-3019)
- Daniel J. Klein (ORCID: https://orcid.org/0000-0002-3533-3273)
- Meng Tao (ORCID: https://orcid.org/0000-0003-3227-9600)
- Giovanna Scapin (ORCID: https://orcid.org/0000-0002-0724-2286)
- Henry S. Lange (ORCID: https://orcid.org/0000-0001-6271-2597)
- Min Xu (ORCID: https://orcid.org/0000-0002-0121-7397)
- Scott S. Walker (ORCID: https://orcid.org/0000-0002-3076-439X)
- Chengwei Wu
- Jason W. Skudlarek (ORCID: https://orcid.org/0000-0002-5847-9144)
- Pamela Shen (ORCID: https://orcid.org/0000-0002-3187-8567)
- Andrew Leithead
- Marc Labroli (ORCID: https://orcid.org/0000-0003-0701-9057)
- Ling Tong (ORCID: https://orcid.org/0000-0003-3302-8184)
- Yun-Ting Chen
- Li‐Kang Zhang (ORCID: https://orcid.org/0000-0003-3757-8116)
- Alexei V. Buevich (ORCID: https://orcid.org/0000-0002-5968-9151)
- Marina Bukhtiyarova (ORCID: https://orcid.org/0000-0002-5520-6458)
- R.K. Cheng (ORCID: https://orcid.org/0000-0001-7564-1230)
- David McKenney
- Douglas C. Beshore (ORCID: https://orcid.org/0000-0001-9746-1863)
- Liudmila Dzhekieva
- Jonathan M. E. Hughes (ORCID: https://orcid.org/0000-0002-5708-2882)
- Kerim Babaoglu (ORCID: https://orcid.org/0000-0002-0937-3191)
- Deyou Sha
- Jian Liu (ORCID: https://orcid.org/0000-0001-5548-1858)
- Hao Wang
- Randy R. Miller (ORCID: https://orcid.org/0000-0003-4695-7994)
- Helen J. Mitchell
- Andrew Cooke
- Anthony W. Shaw
Institutions
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-08-22
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01277
- Citations
- 5
- Primary Topic
- Antibiotic Resistance in Bacteria
- Type
- article
- Field-Weighted Citation Impact
- 0.85