title: RecA Inhibitors Potentiate Antibiotic Activity and Block Evolution of Antibiotic Resistance.
abstract: Antibiotic resistance arises from the maintenance of resistance mutations or genes acquired from the acquisition of adaptive de novo mutations or the transfer of resistance genes. Antibiotic resistance is acquired in response to antibiotic therapy by activating SOS-mediated DNA repair and mutagenesis and horizontal gene transfer pathways. Initiation of the SOS pathway promotes activation of RecA, inactivation of LexA repressor, and induction of SOS genes. Here, we have identified and characterized phthalocyanine tetrasulfonic acid RecA inhibitors that block antibiotic-induced activation of the SOS response. These inhibitors potentiate the activity of bactericidal antibiotics, including members of the quinolone, β-lactam, and aminoglycoside families in both Gram-negative and Gram-positive bacteria. They reduce the ability of bacteria to acquire antibiotic resistance mutations and to transfer mobile genetic elements conferring resistance. This study highlights the advantage of including RecA inhibitors in bactericidal antibiotic therapies and provides a new strategy for prolonging antibiotic shelf life.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
authors.forename: Md Kausar
authors.initials: MK
authors.lastname: Alam
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
authors.forename: Areej
authors.initials: A
authors.lastname: Alhhazmi
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
authors.forename: John F
authors.initials: JF
authors.lastname: DeCoteau
authors.affiliation: Department of Biochemistry, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
authors.forename: Yu
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada. Electronic address: ron.geyer@usask.ca.
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Geyer
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D004352:Drug Resistance, Microbial / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000201:enzymology; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000201:enzymology; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011938:Rec A Recombinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D007211:Indoles; C028418:tetrasulfophthalocyanine; D011938:Rec A Recombinases