Giuseppe
Emeritus
[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]
New β-lactamase inhibitors: A therapeutic renaissance in an ?MDR world?!
Sarah M. Drawz 1, Krisztina M. Papp-Wallace 2,3 and Robert A. Bonomo 2,3,4,5,6*
Author Affiliations: <SUP>1</SUP>Department of Lab Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA <SUP>2</SUP>Research Service, Louis Stokes Cleveland Department of Veterans Affairs, Cleveland, OH, USA <SUP>3</SUP>Departments of Medicine <SUP>4</SUP>Biochemistry <SUP>5</SUP>Pharmacology <SUP>6</SUP>Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, OH, USA
ABSTRACT
As the incidence of Gram-negative bacterial infections to which few effective treatments remain increases, so does the contribution of drug hydrolyzing β-lactamase enzymes to this serious clinical problem. This review highlights recent advances in β-lactamase inhibitors and focuses on agents with novel mechanisms of action against a wide range of enzymes. To this end, we review the β-lactamase inhibitors currently in clinical trials, select agents still in pre-clinical development, and older therapeutic approaches that are being revisited. Particular emphasis is placed on the activity of compounds at the forefront of the developmental pipeline, including the diazabicyclooctane inhibitors (avibactam and MK-7655), and the boronate, RPX7009. With its novel reversible mechanism, avibactam stands to be the first new β-lactamase inhibitor brought into clinical use in the past two decades. Our discussion also includes strategies for selecting the appropriate partner β-lactam and dosing regimens for these promising agents. In lastly, we illustrate how modern techniques for modeling and optimizing drug targets can translate their impact even more widely than before. This ?renaissance? of β-lactamase inhibitors offers new hope in a world plagued by multidrug-resistant (MDR) Gram-negative bacteria.
FOOTNOTES
*Corresponding author: Robert A. Bonomo, MD, Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, 10701 East Blvd., Cleveland, OH 44106, USA, Ph: 2167913800 x4399, Email: robert.bonomo@med.va.gov
Copyright ? 2013, American Society for Microbiology. All Rights Reserved.
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New β-lactamase inhibitors: A therapeutic renaissance in an ?MDR world?!
Sarah M. Drawz 1, Krisztina M. Papp-Wallace 2,3 and Robert A. Bonomo 2,3,4,5,6*
Author Affiliations: <SUP>1</SUP>Department of Lab Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA <SUP>2</SUP>Research Service, Louis Stokes Cleveland Department of Veterans Affairs, Cleveland, OH, USA <SUP>3</SUP>Departments of Medicine <SUP>4</SUP>Biochemistry <SUP>5</SUP>Pharmacology <SUP>6</SUP>Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, OH, USA
ABSTRACT
As the incidence of Gram-negative bacterial infections to which few effective treatments remain increases, so does the contribution of drug hydrolyzing β-lactamase enzymes to this serious clinical problem. This review highlights recent advances in β-lactamase inhibitors and focuses on agents with novel mechanisms of action against a wide range of enzymes. To this end, we review the β-lactamase inhibitors currently in clinical trials, select agents still in pre-clinical development, and older therapeutic approaches that are being revisited. Particular emphasis is placed on the activity of compounds at the forefront of the developmental pipeline, including the diazabicyclooctane inhibitors (avibactam and MK-7655), and the boronate, RPX7009. With its novel reversible mechanism, avibactam stands to be the first new β-lactamase inhibitor brought into clinical use in the past two decades. Our discussion also includes strategies for selecting the appropriate partner β-lactam and dosing regimens for these promising agents. In lastly, we illustrate how modern techniques for modeling and optimizing drug targets can translate their impact even more widely than before. This ?renaissance? of β-lactamase inhibitors offers new hope in a world plagued by multidrug-resistant (MDR) Gram-negative bacteria.
FOOTNOTES
*Corresponding author: Robert A. Bonomo, MD, Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, 10701 East Blvd., Cleveland, OH 44106, USA, Ph: 2167913800 x4399, Email: robert.bonomo@med.va.gov
Copyright ? 2013, American Society for Microbiology. All Rights Reserved.
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