title: Structure-activity relationship-based screening of antibiotics against Gram-negative Acinetobacter baumannii.
abstract: To discover potent antibiotics against the Gram-negative bacteria, we performed a structure-activity relationship (SAR) study of YKsa-6, which was the most potent inhibitor of Staphylococcus aureus β-ketoacyl acyl carrier protein III in our previous study. We identified and selected 11 candidates, and finally screened two active compounds, YKab-4 (4-[(3-chloro-4-methylphenyl)aminoiminomethyl]benzene-1,3-diol) and YKab-6 (4-[[3-(trifluoromethyl)phenyl]aminoiminomethyl]phenol) as inhibitors of Acinetobacter baumannii KAS III (abKAS III). They showed potent antimicrobial activities at 2 or 8 μg/mL, specifically against Acinetobacter baumannii and a strong binding affinity for abKAS III. From the homology modeling, we defined the three-dimensional (3D) structure of abKAS III for the first time and found that it had an extra loop region compared with common Gram-negative bacteria derived KAS IIIs. The docking study revealed that the hydroxyl groups of inhibitors formed extensive hydrogen bonds and the complicated hydrophobic and cation-stacking interactions are important to binding with abKAS III. We confirmed that the hydrophobicity of these compounds might be the essential factor for their antimicrobial activities against Gram-negative bacteria as well as their structural rigidity, a cooperative feature for retaining the hydrophobic interactions between abKAS III and its inhibitors. This study may provide an insight developing strategies for potent antibiotics against A. baumannii.
authors.affiliation: In silico Molecular Design Team, Chemical Occasion by Modeling Alchemy (CheOMA), Anyang-si 14067, Republic of Korea.
authors.forename: Jee-Young
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea.
authors.forename: Min-Cheol
authors.initials: MC
authors.lastname: Jeong
authors.affiliation: Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea.
authors.forename: Dasom
authors.initials: D
authors.lastname: Jeon
authors.affiliation: Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea.
authors.forename: Yeongjun
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea.
authors.forename: Woo Cheol
authors.initials: WC
authors.lastname: Lee
authors.affiliation: Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea. Electronic address: ymkim@konkuk.ac.kr.
authors.forename: Yangmee
authors.initials: Y
authors.lastname: Kim
mesh_terms: D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000037:antagonists & inhibitors; D040981:Acinetobacter baumannii / Q000187:drug effects*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology*; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D062105:Molecular Docking Simulation; D009573:Nitrites / Q000378:metabolism; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D012118:Resorcinols / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D006835:Hydrazones; D009573:Nitrites; D010636:Phenols; D012333:RNA, Messenger; D012118:Resorcinols; C000625537:YKSA-4 compound; C000625536:YKSA-6 compound; C077402:3-ketoacyl-acyl carrier protein synthase III; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase
keywords: Antibiotics; Fatty acid synthesis; Gram-negative bacteria; In silico screening; KAS