title: Novel fluorinated pyrrolomycins as potent anti-staphylococcal biofilm agents: Design, synthesis, pharmacokinetics and antibacterial activities.
abstract: Staphylococcus aureus (SA) is a major cause of hospital- and community-associated bacterial infections in the U.S. and around the world. These infections have become increasingly difficult to treat due to the propensity to develop antibiotic resistance and form biofilm. To date, no antibiofilm agents are available for clinical use. To add to the repertoire of antibiotics for clinical use and to provide novel agents for combating both SA and biofilm infections, we previously reported marinopyrroles as potent anti-SA agents. In this study, we used fragment-based and bioisostere approaches to design and synthesize a series of novel fluorinated pyrrolomycins for the first time, performed analyses of their physicochemical and drug-like properties, and investigated structure activity relationships and pharmacokinetics. These promising fluorinated pyrrolomycins demonstrate potent antibacterial activity against SA with favorable drug-like properties and pharmacokinetic profiles. Importantly, these compounds kill staphylococcal biofilm-associated cells with a lack of mammalian cell cytotoxicity and no occurrence of bacterial resistance. Our novel fluorinated pyrrolomycin 4 has a clogP value of 4.1, an MIC of 73 ng/mL, MBC of 4 μg/mL, kill staphylococcal-associated biofilm at 8 μg/mL, bioavailability of 35%, and the elimination half-life of 6.04 h and 6.75 h by intravenous and oral administration, respectively. This is the first report of comprehensive drug discovery studies on pyrrolomycin-based antibiotics.
authors: UNMC Center for Drug Discovery and Department of Pharmaceutical Sciences, United States.
authors: Zunhua
authors: Z
authors: Yang
authors: UNMC Center for Drug Discovery and Department of Pharmaceutical Sciences, United States.
authors: Yan
authors: Y
authors: Liu
authors: Department of Pathology and Microbiology, United States.
authors: Jongsam
authors: J
authors: Ahn
authors: UNMC Center for Drug Discovery and Department of Pharmaceutical Sciences, United States.
authors: Zhen
authors: Z
authors: Qiao
authors: Department of Pathology and Microbiology, United States.
authors: Jennifer L
authors: JL
authors: Endres
authors: UNMC Center for Drug Discovery and Department of Pharmaceutical Sciences, United States.
authors: Nagsen
authors: N
authors: Gautam
authors: Department of Pharmacology and Experimental Neuroscience, United States.
authors: Yunlong
authors: Y
authors: Huang
authors: UNMC Center for Drug Discovery and Department of Pharmaceutical Sciences, United States.
authors: Jerry
authors: J
authors: Li
authors: Department of Pathology and Microbiology, United States; Department of Pharmacology and Experimental Neuroscience, United States.
authors: Jialin
authors: J
authors: Zheng
authors: UNMC Center for Drug Discovery and Department of Pharmaceutical Sciences, United States.
authors: Yazen
authors: Y
authors: Alnouti
authors: Department of Pathology and Microbiology, United States; Center for Staphylococcal Research, United States.
authors: Kenneth W
authors: KW
authors: Bayles
authors: UNMC Center for Drug Discovery and Department of Pharmaceutical Sciences, United States; Center for Staphylococcal Research, United States; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, 986125 Nebraska Medical Center, Omaha, NE 68198, United States. Electronic address: Rongshi.li@unmc.edu.
authors: Rongshi
authors: R
authors: Li
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D018441:Biofilms / Q000187:drug effects*; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D054879:Halogenation; D006367:HeLa Cells; D006801:Humans; D011758:Pyrroles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000502:physiology*
chemical_list: D000900:Anti-Bacterial Agents; D011758:Pyrroles
keywords: Antibiofilm; Antibiotic drug discovery; Pyrrolomycin; SAR optimization; Staphylococcus aureus