title: Holarrhena antidysenterica Extract and Its Steroidal Alkaloid, Conessine, as Resistance-Modifying Agents Against Extensively Drug-Resistant Acinetobacter baumannii.
abstract: Emergence and spread of antibiotic-resistant Acinetobacter baumannii have become a major public health concern. This study was designed to investigate the efficacy of Holarrhena antidysenterica extract and its major steroidal alkaloid conessine as resistance-modifying agents (RMAs) on the susceptibility of A. baumannii to novobiocin and rifampicin. A significant synergistic activity of both the extract and conessine in combination with either novobiocin or rifampicin with fractional inhibitory concentration index ≤0.5 was demonstrated. Fluorescent dyes and different efflux pump inhibitors were used to further investigate the synergism. Increase in the uptake of 1-N-phenylnaphthylamine in the bacterial cells treated with the extract and conessine was not observed indicating that both substances did not act as permeabilizers. With regard to efflux pump inhibition, no accumulation in ethidium bromide (EtBr) was noticed suggesting that the AdeABC pump was not involved. In contrast, accumulation in Pyronin Y was significantly increased (p < 0.05) demonstrating that the synergism was due to interference with the AdeIJK pump. Study on frequencies of the spontaneous mutational resistance to the extract in combination with antibiotics demonstrated attenuation in drug-resistant organisms. Thus, H. antidysenterica extract and conessine as RMAs may offer a combinatory therapy to restore antibiotic susceptibility in the extensively drug-resistant A. baumannii.
authors.affiliation: 1 Department of Microbiology and Excellence Research Laboratory on Natural Products, Faculty of Science and Natural Product Research Center of Excellence, Prince of Songkla University , Hat Yai, Thailand .
authors.forename: Thanyaluck
authors.initials: T
authors.lastname: Siriyong
authors.affiliation: 2 Faculty of Traditional Thai Medicine and Excellence Research Laboratory on Natural Products, Faculty of Science and Natural Product Research Center of Excellence, Prince of Songkla University , Hat Yai, Thailand .
authors.forename: Sasitorn
authors.initials: S
authors.lastname: Chusri
authors.affiliation: 3 Graduate Program, Faculty of Allied Health Sciences, Thammasat University , Pathumthani, Thailand .
authors.forename: Potjanee
authors.initials: P
authors.lastname: Srimanote
authors.affiliation: 4 Department of Biomedical Sciences, Faculty of Medicine, Prince of Songkla University , Hat Yai, Thailand .
authors.forename: Varomyalin
authors.initials: V
authors.lastname: Tipmanee
authors.affiliation: 1 Department of Microbiology and Excellence Research Laboratory on Natural Products, Faculty of Science and Natural Product Research Center of Excellence, Prince of Songkla University , Hat Yai, Thailand .
authors.forename: Supayang Piyawan
authors.initials: SP
authors.lastname: Voravuthikunchai
mesh_terms: D015057:1-Naphthylamine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000302:isolation & purification; D000470:Alkaloids / Q000302:isolation & purification / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects* / Q000235:genetics; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004996:Ethidium / Q000378:metabolism; D035462:Holarrhena / Q000737:chemistry*; D006801:Humans; D008826:Microbial Sensitivity Tests; D009675:Novobiocin / Q000494:pharmacology*; D010936:Plant Extracts / Q000737:chemistry; D011754:Pyronine / Q000378:metabolism; D012293:Rifampin / Q000494:pharmacology*
chemical_list: D000470:Alkaloids; D000900:Anti-Bacterial Agents; D010936:Plant Extracts; D009675:Novobiocin; C005444:N-phenyl-1-naphthylamine; D015057:1-Naphthylamine; D004996:Ethidium; C007111:conessine; D012293:Rifampin; D011754:Pyronine