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

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, which have served as scaffolds for important antibacterial drugs like metronidazole and the quinolones.  In this review we highlight other alkaloids with development potential.  Natural, semi-synthetic, 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 MICs of 0.1 ng/mL against Helicobacter pylori, and squalamine, a polyamine alkaloid from the dogfish shark which 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 like 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 colonization.  The review concludes with implications and limitations of the described research, and directions for future research.