title: In vivo efficacy and synergistic interaction of 16α-hydroxycleroda-3, 13 (14) Z-dien-15, 16-olide, a clerodane diterpene from Polyalthia longifolia against methicillin-resistant Staphylococcus aureus.
abstract: The Staphylococcus aureus bacterium, a nosocomial pathogen often causing untreatable and lethal infection in patients, mutated to become resistant to all the first-line drugs. The present study details the potential of clerodane diterpene 16α-hydroxycleroda-3, 13 (14) Z-dien-15, 16-olide (CD) isolated from Polyalthia longifolia against methicillin-resistant S. aureus (MRSA) through in vitro and in vivo assays. Minimum inhibitory concentration (MIC) of CD exhibited significant anti-MRSA activity (15.625-31.25 mg/l) against reference strain and seven clinical isolates, while time kill assays at graded MICs indicated 2.78-9.59- and 2.9-6.18-fold reduction in growth of reference strain and clinical isolates of S. aureus, respectively. The combined effect of the CD and 7.5 % NaCl resulted in significant reduction in microbial count within 24 h, indicating the loss of the salt tolerance ability of S. aureus. Further, release of 260-nm absorbing material and flow cytometric analysis revealed an increased uptake of propidium iodide. These assays may indicate the membrane-damaging potential of CD. The molecule CD was found to interact synergistically with clinically used antibiotics (FICI ≤ 0.5) against all clinical isolates. In infected mice, CD significantly (P < 0.001) lowered the systemic microbial load in blood, liver, kidney, lung and spleen tissues and did not exhibit any significant toxicity at 100 mg/kg body weight.
authors.affiliation: CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow, 226 015, India.
authors.forename: Vivek Kumar
authors.initials: VK
authors.lastname: Gupta
authors.forename: Surjeet
authors.initials: S
authors.lastname: Verma
authors.forename: Anirban
authors.initials: A
authors.lastname: Pal
authors.forename: Santosh Kumar
authors.initials: SK
authors.lastname: Srivastava
authors.forename: Pramod Kumar
authors.initials: PK
authors.lastname: Srivastava
authors.forename: Mahendra P
authors.initials: MP
authors.lastname: Darokar
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000378:metabolism; D045785:Diterpenes, Clerodane / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development; D051379:Mice; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D008969:Molecular Sequence Data; D031044:Polyalthia / Q000737:chemistry* / Q000378:metabolism; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000900:Anti-Bacterial Agents; D045785:Diterpenes, Clerodane