title: Tetracyclic indolines as a novel class of β-lactam-selective resistance-modifying agent for MRSA.
abstract: Antibiotic-resistant bacterial infections have seen a marked increase in recent years, while antibiotic discovery has waned. Resistance-modifying agents (RMA) offer an intriguing alternative strategy to fight against resistant bacteria. Here we report the discovery, antibiotic profiling, and structure-activity relationships of a novel class of RMAs, tetracyclic indolines. These selectively potentiate β-lactam antibiotics in methicillin-resistant Staphylococcus aureus (MRSA) without antibacterial or β-lactamase inhibitory activity on their own. The most potent analogue, 6a, showed strong potentiation of amoxicillin/clavulanic acid in a variety of hospital-acquired and community-acquired MRSA strains with low mammalian toxicity. These compounds may be further developed to extend the clinic life span of β-lactam antibiotics.
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Yugen
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Lakota
authors.initials: L
authors.lastname: Cleaver
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Jessica D
authors.initials: JD
authors.lastname: Podoll
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Shane
authors.initials: S
authors.lastname: Walls
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Austin
authors.initials: A
authors.lastname: Jolly
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USA. Electronic address: xiang.wang@colorado.edu.
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017714:Community-Acquired Infections / Q000188:drug therapy / Q000382:microbiology; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D004357:Drug Synergism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship; D013754:Tetracyclines / Q000494:pharmacology*; D047090:beta-Lactams / Q000819:agonists* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D007211:Indoles; D013754:Tetracyclines; D047090:beta-Lactams; C057812:indoline
keywords: Antibiotic resistance; Indoline alkaloids; Methicillin-resistant Staphylococcus aureus; Resistance-modifying agent; Structure-activity relationship; β-lactam