Cerastecin Inhibition of the Lipooligosaccharide Transporter MsbA to Combat Acinetobacter baumannii: From Screening Impurity to In Vivo Efficacy

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posted on 2024-08-22, 15:10 authored by Jason W. Skudlarek, Andrew J. Cooke, Helen J. Mitchell, Kerim Babaoglu, Anthony W. Shaw, Ling Tong, Ashley B. Nomland, Marc Labroli, Deyou Sha, James J. Mulhearn, Chengwei Wu, Sarah W. Li, Douglas C. Beshore, Jonathan M. E. Hughes, Matthieu Jouffroy, Hao Wang, Carl J. Balibar, Ronald E. Painter, Pamela Shen, Henry S. Lange, Andrii Ishchenko, Yun-Ting Chen, Daniel J. Klein, Rodger W. Tracy, Randy R. Miller, Tamara D. Cabalu, Zhe Wu, Andrew Leithead, Giovanna Scapin, Alan W. Hruza, Liudmila Dzhekieva, Marina Bukhtiyarova, Michelle F. Homsher, Min Xu, Carolyn Bahnck-Teets, David McKenney, Alexei V. Buevich, Jian Liu, Li-Kang Zhang, Tao Meng, Terri Kelly, Edward DiNunzio, Stephen Soisson, Robert K. Y. Cheng, Michael Hennig, Izzat Raheem, Scott S. Walker

Acinetobacter baumannii, 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 A. baumannii 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 1 (cerastecin D), which exhibited antibacterial activity in the presence of human serum and a pharmacokinetic profile sufficient to achieve efficacy against A. baumannii in murine septicemia and lung infection models.