title: Alkaloids: an overview of their antibacterial, antibiotic-enhancing and antivirulence activities.
abstract: With reports of pandrug-resistant bacteria causing untreatable infections, the need for new antibacterial therapies is more pressing than ever. Alkaloids are a large and structurally diverse group of compounds that have served as scaffolds for important antibacterial drugs such as metronidazole and the quinolones. In this review, we highlight other alkaloids with development potential. Natural, semisynthetic and synthetic alkaloids of all classes are considered, looking first at those with direct antibacterial activity and those with antibiotic-enhancing activity. Potent examples include CJ-13,136, a novel actinomycete-derived quinolone alkaloid with a minimum inhibitory concentration of 0.1 ng/mL against Helicobacter pylori, and squalamine, a polyamine alkaloid from the dogfish shark that renders Gram-negative pathogens 16- to >32-fold more susceptible to ciprofloxacin. Where available, information on toxicity, structure-activity relationships, mechanisms of action and in vivo activity is presented. The effects of alkaloids on virulence gene regulatory systems such as quorum sensing and virulence factors such as sortases, adhesins and secretion systems are also described. The synthetic isoquinoline alkaloid virstatin, for example, inhibits the transcriptional regulator ToxT in Vibrio cholerae, preventing expression of cholera toxin and fimbriae and conferring in vivo protection against intestinal colonisation. The review concludes with implications and limitations of the described research and directions for future research.
authors.affiliation: Faculty of Medicine, Mahasarakham University, Khamriang, Kantarawichai, Maha Sarakham 44150, Thailand. Electronic address: t_cushnie@hotmail.com.
authors.forename: T P Tim
authors.initials: TP
authors.lastname: Cushnie
authors.affiliation: Faculty of Pharmacy, Mahasarakham University, Khamriang, Kantarawichai, Maha Sarakham 44150, Thailand.
authors.forename: Benjamart
authors.initials: B
authors.lastname: Cushnie
authors.affiliation: School of Pharmacy and Life Sciences, Research Institute for Health and Wellbeing, Robert Gordon University, Riverside East, Garthdee Road, Aberdeen AB10 7GJ, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lamb
mesh_terms: D000470:Alkaloids / Q000494:pharmacology* / Q000633:toxicity; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000633:toxicity; D001419:Bacteria / Q000187:drug effects* / Q000254:growth & development / Q000472:pathogenicity; D004357:Drug Synergism; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship; D014774:Virulence / Q000187:drug effects
chemical_list: D000470:Alkaloids; D000900:Anti-Bacterial Agents
keywords: Alkaloid; Antibacterial; Antivirulence; Mechanism of action; Structure–activity; Synergy