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Pharmacology

First Penicillin-Binding Protein Occupancy Patterns for 15 β-Lactams and β-Lactamase Inhibitors in Mycobacterium abscessus

Alaa R. M. Sayed, Nirav R. Shah, Kari B. Basso, Manasi Kamat, Yuanyuan Jiao, Bartolome Moya, Dhruvitkumar S. Sutaria, Yinzhi Lang, Xun Tao, Weiguo Liu, Eunjeong Shin, Jieqiang Zhou, Carolin Werkman, Arnold Louie, George L. Drusano, Jürgen B. Bulitta
Alaa R. M. Sayed
aDepartment of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Orlando, Florida, USA
bDepartment of Chemistry, Faculty of Science, Fayoum University, Fayoum, Egypt
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Nirav R. Shah
aDepartment of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Orlando, Florida, USA
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Kari B. Basso
cDepartment of Chemistry, University of Florida, Gainesville, Florida, USA
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Manasi Kamat
cDepartment of Chemistry, University of Florida, Gainesville, Florida, USA
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Yuanyuan Jiao
aDepartment of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Orlando, Florida, USA
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Bartolome Moya
dServicio de Microbiología, Hospital Universitario Son Espases, Instituto de Investigación Sanitaria Illes Balears, Palma de Mallorca, Spain
eUnidad de Investigación, Hospital Universitario Son Espases, Instituto de Investigación Sanitaria Illes Balears, Palma de Mallorca, Spain
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Dhruvitkumar S. Sutaria
aDepartment of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Orlando, Florida, USA
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Yinzhi Lang
aDepartment of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Orlando, Florida, USA
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Xun Tao
aDepartment of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Orlando, Florida, USA
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Weiguo Liu
fInstitute for Therapeutic Innovation, College of Medicine, University of Florida, Orlando, Florida, USA
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Eunjeong Shin
aDepartment of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Orlando, Florida, USA
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Jieqiang Zhou
aDepartment of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Orlando, Florida, USA
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Carolin Werkman
aDepartment of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Orlando, Florida, USA
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Arnold Louie
fInstitute for Therapeutic Innovation, College of Medicine, University of Florida, Orlando, Florida, USA
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George L. Drusano
fInstitute for Therapeutic Innovation, College of Medicine, University of Florida, Orlando, Florida, USA
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Jürgen B. Bulitta
aDepartment of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Orlando, Florida, USA
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DOI: 10.1128/AAC.01956-20
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ABSTRACT

Mycobacterium abscessus causes serious infections that often require over 18 months of antibiotic combination therapy. There is no standard regimen for the treatment of M. abscessus infections, and the multitude of combinations that have been used clinically have had low success rates and high rates of toxicities. With β-lactam antibiotics being safe, double β-lactam and β-lactam/β-lactamase inhibitor combinations are of interest for improving the treatment of M. abscessus infections and minimizing toxicity. However, a mechanistic approach for building these combinations is lacking since little is known about which penicillin-binding protein (PBP) target receptors are inactivated by different β-lactams in M. abscessus. We determined the preferred PBP targets of 13 β-lactams and 2 β-lactamase inhibitors in two M. abscessus strains and identified PBP sequences by proteomics. The Bocillin FL binding assay was used to determine the β-lactam concentrations that half-maximally inhibited Bocillin binding (50% inhibitory concentrations [IC50s]). Principal component analysis identified four clusters of PBP occupancy patterns. Carbapenems inactivated all PBPs at low concentrations (0.016 to 0.5 mg/liter) (cluster 1). Cephalosporins (cluster 2) inactivated PonA2, PonA1, and PbpA at low (0.031 to 1 mg/liter) (ceftriaxone and cefotaxime) or intermediate (0.35 to 16 mg/liter) (ceftazidime and cefoxitin) concentrations. Sulbactam, aztreonam, carumonam, mecillinam, and avibactam (cluster 3) inactivated the same PBPs as cephalosporins but required higher concentrations. Other penicillins (cluster 4) specifically targeted PbpA at 2 to 16 mg/liter. Carbapenems, ceftriaxone, and cefotaxime were the most promising β-lactams since they inactivated most or all PBPs at clinically relevant concentrations. These first PBP occupancy patterns in M. abscessus provide a mechanistic foundation for selecting and optimizing safe and effective combination therapies with β-lactams.

FOOTNOTES

    • Received 11 September 2020.
    • Returned for modification 16 October 2020.
    • Accepted 21 October 2020.
    • Accepted manuscript posted online 26 October 2020.
  • Supplemental material is available online only.

  • Copyright © 2020 American Society for Microbiology.

All Rights Reserved.

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First Penicillin-Binding Protein Occupancy Patterns for 15 β-Lactams and β-Lactamase Inhibitors in Mycobacterium abscessus
Alaa R. M. Sayed, Nirav R. Shah, Kari B. Basso, Manasi Kamat, Yuanyuan Jiao, Bartolome Moya, Dhruvitkumar S. Sutaria, Yinzhi Lang, Xun Tao, Weiguo Liu, Eunjeong Shin, Jieqiang Zhou, Carolin Werkman, Arnold Louie, George L. Drusano, Jürgen B. Bulitta
Antimicrobial Agents and Chemotherapy Dec 2020, 65 (1) e01956-20; DOI: 10.1128/AAC.01956-20

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First Penicillin-Binding Protein Occupancy Patterns for 15 β-Lactams and β-Lactamase Inhibitors in Mycobacterium abscessus
Alaa R. M. Sayed, Nirav R. Shah, Kari B. Basso, Manasi Kamat, Yuanyuan Jiao, Bartolome Moya, Dhruvitkumar S. Sutaria, Yinzhi Lang, Xun Tao, Weiguo Liu, Eunjeong Shin, Jieqiang Zhou, Carolin Werkman, Arnold Louie, George L. Drusano, Jürgen B. Bulitta
Antimicrobial Agents and Chemotherapy Dec 2020, 65 (1) e01956-20; DOI: 10.1128/AAC.01956-20
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KEYWORDS

penicillin-binding proteins
Mycobacterium abscessus
drug-resistant bacteria
beta-lactams
receptor binding
principal component analysis
cell wall biosynthesis
PonA2
PonA1
PbpA

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