Title

Optimization and Mechanistic Characterization of Pyridopyrimidine Inhibitors of Bacterial Biotin Carboxylase

Authors

Logan D. Andrews, Former employee of Achaogen Inc. , 1 Tower Place, Suite 400 , South San Francisco , California 94080 , United States.
Timothy R. Kane, Former employee of Achaogen Inc. , 1 Tower Place, Suite 400 , South San Francisco , California 94080 , United States.
Paola Dozzo, Former employee of Achaogen Inc. , 1 Tower Place, Suite 400 , South San Francisco , California 94080 , United States.
Cat M. Haglund, Former employee of Achaogen Inc. , 1 Tower Place, Suite 400 , South San Francisco , California 94080 , United States.
Darin J. Hilderbrandt, Former employee of Achaogen Inc. , 1 Tower Place, Suite 400 , South San Francisco , California 94080 , United States.
Martin S. Linsell, Former employee of Achaogen Inc. , 1 Tower Place, Suite 400 , South San Francisco , California 94080 , United States.
Timothy Machajewski, Former employee of Achaogen Inc. , 1 Tower Place, Suite 400 , South San Francisco , California 94080 , United States.
Glen McEnroe, Former employee of Achaogen Inc. , 1 Tower Place, Suite 400 , South San Francisco , California 94080 , United States.
Alisa W. Serio, Former employee of Achaogen Inc. , 1 Tower Place, Suite 400 , South San Francisco , California 94080 , United States.
Kenneth B. Wlasichuk, Former employee of Achaogen Inc. , 1 Tower Place, Suite 400 , South San Francisco , California 94080 , United States.
David B. Neau, Northeastern Collaborative Access Team , Argonne National Laboratory , Argonne , Illinois 60439 , United States.
Svetlana Pakhomova, Department of Biological Sciences , Louisiana State University , Baton Rouge , Louisiana 70803 , United States.
Grover L. Waldrop, Department of Biological Sciences , Louisiana State University , Baton Rouge , Louisiana 70803 , United States.
Marc Sharp, Linnaeus Bioscience Inc. , 3210 Merryfield Row , San Diego , California 92121 , United States.
Joe Pogliano, Linnaeus Bioscience Inc. , 3210 Merryfield Row , San Diego , California 92121 , United States.
Ryan T. Cirz, Former employee of Achaogen Inc. , 1 Tower Place, Suite 400 , South San Francisco , California 94080 , United States.
Frederick Cohen, Former employee of Achaogen Inc. , 1 Tower Place, Suite 400 , South San Francisco , California 94080 , United States.

Document Type

Article

Publication Date

8-22-2019

Abstract

A major challenge for new antibiotic discovery is predicting the physicochemical properties that enable small molecules to permeate Gram-negative bacterial membranes. We have applied physicochemical lessons from previous work to redesign and improve the antibacterial potency of pyridopyrimidine inhibitors of biotin carboxylase (BC) by up to 64-fold and 16-fold against and , respectively. Antibacterial and enzyme potency assessments in the presence of an outer membrane-permeabilizing agent or in efflux-compromised strains indicate that penetration and efflux properties of many redesigned BC inhibitors could be improved to various extents. Spontaneous resistance to the improved pyridopyrimidine inhibitors in occurs at very low frequencies between 10 and 10. However, resistant isolates had alarmingly high minimum inhibitory concentration shifts (16- to >128-fold) compared to the parent strain. Whole-genome sequencing of resistant isolates revealed that either BC target mutations or efflux pump overexpression can lead to the development of high-level resistance.

Publication Source (Journal or Book title)

Journal of medicinal chemistry

First Page

7489

Last Page

7505

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