Abstract

Multidrug-resistant (MDR) bacterial infections are a serious threat to public health. Among the most alarming resistance trends is the rapid rise in the number and diversity of β-lactamases, enzymes that inactivate β-lactams, a class of antibiotics that has been a therapeutic mainstay for decades. Although several new β-lactamase inhibitors have been approved or are in clinical trials, their spectra of activity do not address MDR pathogens such as Acinetobacter baumannii. This report describes the rational design and characterization of expanded-spectrum serine β-lactamase inhibitors that potently inhibit clinically relevant class A, C and D β-lactamases and penicillin-binding proteins, resulting in intrinsic antibacterial activity against Enterobacteriaceae and restoration of β-lactam activity in a broad range of MDR Gram-negative pathogens. One of the most promising combinations is sulbactam–ETX2514, whose potent antibacterial activity, in vivo efficacy against MDR A. baumannii infections and promising preclinical safety demonstrate its potential to address this significant unmet medical need.

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Acknowledgements

The authors thank the following groups and individuals: the AstraZeneca Infection medicinal chemistry team, especially B. Geng, H. Xiong, Y. Wu and F. Wu for their contributions to this project; S. Tentarelli, L. Gauthier, T. Friedman and C. Joubran for their assistance with analytical chemistry; H. Jahić for biochemical testing; J. Whiteaker for generating whole-genome sequencing data; J. Verheijen for partner discussions and P. Miller and P. Bradford for their leadership at AstraZeneca. The authors acknowledge the Novexel chemistry and biology teams for scientific discussions and insights into the DBO scaffold, and our collaborators at Syngene and Pharmaron for synthesis and at IHMA for susceptibility testing. The authors thank P. Dunman for the plasmid used in the A. baumannii isogenic panel. Finally, the authors thank M. Perros for his leadership both at AstraZeneca and Entasis and his comments on this manuscript. This work was fully funded by AstraZeneca and Entasis Therapeutics.

Author information

Author notes

    • Neil Bifulco
    • , Hoan Huynh
    • , Sushmita Lahiri
    • , Jason Thresher
    • , Tiffany Palmer
    • , Robert A. Giacobbe
    • , Joseph V. Newman
    • , David E. Ehmann
    •  & Boudewijn de Jonge

    Present addresses: Blueprint Medicines, 38 Sidney Street, Cambridge, Massachusetts 02139, USA (N.B.); Alkermes, 852 Winter Street, Waltham, Massachusetts 02451, USA (H.H.); Macrolide Pharmaceuticals, 480 Arsenal Street, Watertown, Massachusetts 02472, USA (S.L.); Kaleido Biosciences, 47 Moulton Street, Cambridge, Massachusetts 02138, USA (J.T.); Moderna Therapeutics, 320 Bent Street, Cambridge, Massachusetts 02141, USA (T.P.); WarpDriveBio, 400 Technology Square, Cambridge, Massachusetts 02139, USA (R.A.G.); Tetraphase Pharmaceuticals, 480 Arsenal Street, Watertown, Massachusetts 02472, USA (J.V.N.); Shire, 300 Shire Way, Lexington, Massachusetts 02421, USA (D.E.E.); Pfizer, 610 Main Street, Cambridge, Massachusetts 02139 (B.D.J.).

Affiliations

  1. Entasis Therapeutics, 35 Gatehouse Drive, Waltham, Massachusetts 02451, USA

    • Thomas F. Durand-Réville
    • , Satenig Guler
    • , Janelle Comita-Prevoir
    • , Adam B. Shapiro
    • , Sarah M. McLeod
    • , Nicole M. Carter
    • , Samir H. Moussa
    • , Camilo Velez-Vega
    • , John O'Donnell
    • , John P. Mueller
    • , Rubén A. Tommasi
    •  & Alita A. Miller
  2. AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, USA

    • Brendan Chen
    • , Neil Bifulco
    • , Hoan Huynh
    • , Sushmita Lahiri
    • , Nelson B. Olivier
    • , Robert McLaughlin
    • , Ning Gao
    • , Jason Thresher
    • , Tiffany Palmer
    • , Beth Andrews
    • , Robert A. Giacobbe
    • , Joseph V. Newman
    • , David E. Ehmann
    •  & Boudewijn de Jonge

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Contributions

T.F.D.-R. led the chemistry teams both at AstraZeneca and Entasis. S.G., J.C.-P., B.C. and N.B. generated the compounds described in the manuscript. H.H. led the lead finding team at AstraZeneca. S.L. solved the structure and performed the crystallographic analysis. C.V.-V. performed computational chemistry studies. N.B.O. performed crystallographic structure refinement and temperature factor analysis. A.B.S. and T.P. were responsible for biochemical data generation and analysis. S.M.M. performed microscopy. S.H.M. performed WGS analysis, constructed the A. baumannii expression vector and isogenic panel, and performed susceptibility testing. S.M.M., N.M.C., B.A. and R.A.G. performed susceptibility testing. R.M. analysed whole-genome sequences. N.G. expressed and purified PBPs. J.T. cloned and expressed β-lactamases and PBPs. J.V.N. led the in vivo efficacy studies. J.O'D. was responsible for the DMPK, PK/PD, in vivo efficacy and preclinical safety testing and wrote sections of the manuscript. D.E.E. and B.D.J. led the biochemistry and microbiology, respectively, at AstraZeneca. J.P.M. and R.A.T. oversaw the project at both AstraZeneca and Entasis. A.A.M. led the biology team at Entasis. T.F.D.-R. and A.A.M. wrote the manuscript.

Competing interests

All authors are current or past employees of AstraZeneca or Entasis Therapeutics and may own stock from one or both companies. Entasis Therapeutics owns a granted patent on the new diazabicyclooctenone BLI series (US patent 9,309,245 B2, granted 12 April 2016).

Corresponding authors

Correspondence to Thomas F. Durand-Réville or Alita A. Miller.

Supplementary information

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    Supplementary Information

    Supplementary Methods 1–4, Supplementary Tables 1–6, Supplementary Figure 1.

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    Supplementary Data 1

    Metadata, β-lactamase content and antibiotic susceptibility of 84 recent MDR A. baumannii clinical isolates.

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DOI

https://doi.org/10.1038/nmicrobiol.2017.104