title: Exploring Synergy between Classic Mutagens and Antibiotics To Examine Mechanisms of Synergy and Antibiotic Action.
abstract: We used classical mutagens in Gram-negative Escherichia coli to study synergies with different classes of antibiotics, test models of antibiotic mechanisms of action, and examine the basis of synergy. We used 4-nitroquinoline 1-oxide (4NQO), zebularine (ZEB), 5-azacytidine (5AZ), 2-aminopurine (2AP), and 5-bromodeoxyuridine (5BrdU) as mutagens (with bactericidal potency of 4NQO > ZEB > 5AZ > 2AP > 5BrdU) and vancomycin (VAN), ciprofloxacin (CPR), trimethoprim (TMP), gentamicin (GEN), tetracycline (TET), erythromycin (ERY), and chloramphenicol (CHL) as antibiotics. We detected the strongest synergies with 4NQO, an agent that oxidizes guanines and ultimately results in double-strand breaks when paired with the bactericidal antibiotics VAN, TMP, CPR, and GEN, but no synergies with the bacteriostatic antibiotics TET, ERY, and CHL. Each of the other mutagens displays synergies with the bactericidal antibiotics to various degrees that reflect their potencies, as well as with some of the other mutagens. The results support recent models showing that bactericidal antibiotics kill bacteria principally by ultimately generating more double-strand breaks than can be repaired. We discuss the synergies seen here and elsewhere as representing dose effects of not the proximal target damage but rather the ultimate resulting double-strand breaks. We also used the results of pairwise tests to place the classic mutagens into functional antibacterial categories within a previously defined drug interaction network.
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, USA Molecular Biology Institute, University of California, Los Angeles, Los Angeles, California, USA David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Lisa Yun
authors.initials: LY
authors.lastname: Song
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, USA Molecular Biology Institute, University of California, Los Angeles, Los Angeles, California, USA David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: D'Souza
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, USA Molecular Biology Institute, University of California, Los Angeles, Los Angeles, California, USA David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Lam
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, USA Molecular Biology Institute, University of California, Los Angeles, Los Angeles, California, USA David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Tina Manzhu
authors.initials: TM
authors.lastname: Kang
authors.affiliation: Department of Ecology and Evolutionary Biology, University of California, Los Angeles, Los Angeles, California, USA jhmiller@microbio.ucla.edu pamelayeh@ucla.edu.
authors.forename: Pamela
authors.initials: P
authors.lastname: Yeh
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, USA Molecular Biology Institute, University of California, Los Angeles, Los Angeles, California, USA David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA jhmiller@microbio.ucla.edu pamelayeh@ucla.edu.
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Miller
mesh_terms: D015075:2-Aminopurine / Q000494:pharmacology; D015112:4-Nitroquinoline-1-oxide / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001374:Azacitidine / Q000494:pharmacology; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002701:Chloramphenicol / Q000494:pharmacology; D002939:Ciprofloxacin / Q000494:pharmacology; D003562:Cytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects*; D004357:Drug Synergism; D004917:Erythromycin / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects*; D005839:Gentamicins / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009153:Mutagens / Q000494:pharmacology*; D013752:Tetracycline / Q000494:pharmacology; D014295:Trimethoprim / Q000494:pharmacology; D014640:Vancomycin / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D005839:Gentamicins; D009153:Mutagens; D015075:2-Aminopurine; D015112:4-Nitroquinoline-1-oxide; D003562:Cytidine; D002939:Ciprofloxacin; D004917:Erythromycin; D002701:Chloramphenicol; D014640:Vancomycin; C009131:pyrimidin-2-one beta-ribofuranoside; D014295:Trimethoprim; D013752:Tetracycline; D001973:Bromodeoxyuridine; D001374:Azacitidine