title: Characterizing the Antimicrobial Activity ofN2,N4-Disubstituted Quinazoline-2,4-Diamines toward Multidrug-Resistant Acinetobacter baumannii.
abstract: We previously reported a series ofN2,N4-disubstituted quinazoline-2,4-diamines as dihydrofolate reductase inhibitors with potentin vitroandin vivoantibacterial activity against methicillin-resistantStaphylococcus aureus(MRSA) strains. In this work, we extended our previous study to the Gram-negative pathogenAcinetobacter baumanniiWe determined that optimizedN2,N4-disubstituted quinazoline-2,4-diamines are strongly antibacterial against multidrug-resistantA. baumanniistrains when the 6-position is replaced with a halide or an alkyl substituent. Such agents display potent antibacterial activity, with MICs as low as 0.5 μM, while proving to be strongly bactericidal. Interestingly, these compounds also possess the potential for antibiofilm activity, eradicating 90% of cells within a biofilm at or near MICs. Using serial passage assays, we observed a limited capacity for the development of resistance toward these molecules (4-fold increase in MIC) compared to existing folic acid synthesis inhibitors, such as trimethoprim (64-fold increase) and sulfamethoxazole (128-fold increase). We also identified limited toxicity toward human cells, with 50% lethal doses (LD50s) of ≤23 μM for lead agents 4 and 5. Finally, we demonstrated that our lead agents have excellentin vivoefficacy, with lead agent 5 proving more efficacious than tigecycline in a murine model ofA. baumanniiinfection (90% survival versus 66%), despite being used at a lower dose (2 versus 30 mg kg-1). Together, our results demonstrate thatN2,N4-disubstituted quinazoline-2,4-diamines have strong antimicrobial and antibiofilm activities against both Gram-positive organisms and Gram-negative pathogens, suggesting strong potential for their development as antibacterial agents.
authors.affiliation: Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, Florida, USA.|Center for Drug Discovery and Innovation, University of South Florida, Tampa, Florida, USA.
authors.forename: Renee
authors.initials: R
authors.lastname: Fleeman
authors.affiliation: Department of Chemistry, University of South Florida, Tampa, Florida, USA.
authors.forename: Kurt S
authors.initials: KS
authors.lastname: Van Horn
authors.affiliation: Department of Chemistry, University of South Florida, Tampa, Florida, USA.
authors.forename: Megan M
authors.initials: MM
authors.lastname: Barber
authors.affiliation: Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, Florida, USA.
authors.forename: Whittney N
authors.initials: WN
authors.lastname: Burda
authors.affiliation: Department of Chemistry, University of South Florida, Tampa, Florida, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Flanigan
authors.affiliation: Department of Chemistry and Chemical Biology and Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts, USA r.manetsch@neu.edu shaw@usf.edu.
authors.forename: Roman
authors.initials: R
authors.lastname: Manetsch
authors.affiliation: Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, Florida, USA r.manetsch@neu.edu shaw@usf.edu.|Center for Drug Discovery and Innovation, University of South Florida, Tampa, Florida, USA.
authors.forename: Lindsey N
authors.identifier: 0000-0002-0629-8990
authors.initials: LN
authors.lastname: Shaw
mesh_terms: D000151:Acinetobacter Infections / Q000188:drug therapy / Q000382:microbiology; D040981:Acinetobacter baumannii / Q000187:drug effects*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003959:Diamines / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D024901:Drug Resistance, Multiple, Bacterial; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D051379:Mice; D008826:Microbial Sensitivity Tests; D010538:Peritonitis / Q000188:drug therapy / Q000382:microbiology; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D013762:Tetrahydrofolate Dehydrogenase / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D003959:Diamines; D005493:Folic Acid Antagonists; D011799:Quinazolines; D013762:Tetrahydrofolate Dehydrogenase
keywords: Acinetobacter baumannii; Gram negative antibacterial; biofilm; dihydrofolate reductase inhibitors; quinazoline