Rational design of a new antibiotic class for drug-resistant infections

Thomas F. Durand-Reville, Alita A. Miller, John P. O’Donnell, Xiaoyun Wu, Mark A. Sylvester, Satenig Guler, Ramkumar Iyer, Adam B. Shapiro, Nicole M. Carter, Camilo Velez-Vega, Samir H. Moussa, Sarah M. McLeod, April Chen, Angela M. Tanudra, Jing Zhang, Janelle Comita-Prevoir, Jan A. Romero, Hoan Huynh, Andrew D. Ferguson, Peter S. Horanyi, Stephen J. Mayclin, Henry S. Heine, George L. Drusano, Jason E. Cummings, Richard A. Slayden and Ruben A. Tommasi ()
Additional contact information
Thomas F. Durand-Reville: Entasis Therapeutics
Alita A. Miller: Entasis Therapeutics
John P. O’Donnell: Entasis Therapeutics
Xiaoyun Wu: Novartis Institute for Biomedical Research
Mark A. Sylvester: Entasis Therapeutics
Satenig Guler: Entasis Therapeutics
Ramkumar Iyer: Entasis Therapeutics
Adam B. Shapiro: Entasis Therapeutics
Nicole M. Carter: Entasis Therapeutics
Camilo Velez-Vega: Entasis Therapeutics
Samir H. Moussa: Entasis Therapeutics
Sarah M. McLeod: Entasis Therapeutics
April Chen: Entasis Therapeutics
Angela M. Tanudra: Entasis Therapeutics
Jing Zhang: Entasis Therapeutics
Janelle Comita-Prevoir: Entasis Therapeutics
Jan A. Romero: Entasis Therapeutics
Hoan Huynh: Alkermes
Andrew D. Ferguson: Takeda
Peter S. Horanyi: UCB Boston
Stephen J. Mayclin: UCB Boston
Henry S. Heine: Institute for Therapeutic Innovation
George L. Drusano: Institute for Therapeutic Innovation
Jason E. Cummings: Colorado State University
Richard A. Slayden: Colorado State University
Ruben A. Tommasi: Entasis Therapeutics

Nature, 2021, vol. 597, issue 7878, 698-702

Abstract: Abstract The development of new antibiotics to treat infections caused by drug-resistant Gram-negative pathogens is of paramount importance as antibiotic resistance continues to increase worldwide1. Here we describe a strategy for the rational design of diazabicyclooctane inhibitors of penicillin-binding proteins from Gram-negative bacteria to overcome multiple mechanisms of resistance, including β-lactamase enzymes, stringent response and outer membrane permeation. Diazabicyclooctane inhibitors retain activity in the presence of β-lactamases, the primary resistance mechanism associated with β-lactam therapy in Gram-negative bacteria2,3. Although the target spectrum of an initial lead was successfully re-engineered to gain in vivo efficacy, its ability to permeate across bacterial outer membranes was insufficient for further development. Notably, the features that enhanced target potency were found to preclude compound uptake. An improved optimization strategy leveraged porin permeation properties concomitant with biochemical potency in the lead-optimization stage. This resulted in ETX0462, which has potent in vitro and in vivo activity against Pseudomonas aeruginosa plus all other Gram-negative ESKAPE pathogens, Stenotrophomonas maltophilia and biothreat pathogens. These attributes, along with a favourable preclinical safety profile, hold promise for the successful clinical development of the first novel Gram-negative chemotype to treat life-threatening antibiotic-resistant infections in more than 25 years.

Date: 2021
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DOI: 10.1038/s41586-021-03899-0

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