Alkaloids: an overview of their antibacterial, antibiotic-enhancing and antivirulence activities.

Cushnie, T.P. Tim; Cushnie, Benjamart; Lamb, Andrew J.

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.

Citation

CUSHNIE, T.P.T., CUSHNIE, B. and LAMB, A.J. 2014. Alkaloids: an overview of their antibacterial, anibiotic-enhancing and antivirulence activities. International journal of antimicrobial agents [online], 44(5), pages 377-386. Available from: https://doi.org/10.1016/j.ijantimicag.2014.06.001

• Journal Article Type: Review
• Acceptance Date: Jun 20, 2014
• Online Publication Date: Jul 15, 2014
• Publication Date: Nov 30, 2014
• Deposit Date: Feb 19, 2021
• Publicly Available Date: Sep 5, 2022
• Journal: International journal of antimicrobial agents
• Print ISSN: 0924-8579
• Electronic ISSN: 1872-7913
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 44
• Issue: 5
• Pages: 377-386
• DOI: https://doi.org/10.1016/j.ijantimicag.2014.06.001
• Keywords: Alkaloid; Antibacterial; Structure–activity; Mechanism of action; Synergy; Antivirulence
• Public URL: https://rgu-repository.worktribe.com/output/1168236
• Additional Information: This article has been published with separate supporting information. This supporting information has been incorporated into a single file on this repository and can be found at the end of this document.