Alkaloids: an Overview of Their Antibacterial, Antibiotic-Enhancing and Antivirulence Activities
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International Journal of Antimicrobial Agents 44 (2014) 377–386 Contents lists available at ScienceDirect International Journal of Antimicrobial Agents j ournal homepage: http://www.elsevier.com/locate/ijantimicag Review Alkaloids: An overview of their antibacterial, antibiotic-enhancing and antivirulence activities a,∗ b c T.P. Tim Cushnie , Benjamart Cushnie , Andrew J. Lamb a Faculty of Medicine, Mahasarakham University, Khamriang, Kantarawichai, Maha Sarakham 44150, Thailand b Faculty of Pharmacy, Mahasarakham University, Khamriang, Kantarawichai, Maha Sarakham 44150, Thailand c School of Pharmacy and Life Sciences, Research Institute for Health and Wellbeing, Robert Gordon University, Riverside East, Garthdee Road, Aberdeen AB10 7GJ, UK a r t i c l e i n f o a b s t r a c t Article history: With reports of pandrug-resistant bacteria causing untreatable infections, the need for new antibac- Received 16 June 2014 terial therapies is more pressing than ever. Alkaloids are a large and structurally diverse group of Accepted 20 June 2014 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, Keywords: semisynthetic and synthetic alkaloids of all classes are considered, looking first at those with direct Alkaloid antibacterial activity and those with antibiotic-enhancing activity. Potent examples include CJ-13,136, a Antibacterial novel actinomycete-derived quinolone alkaloid with a minimum inhibitory concentration of 0.1 ng/mL Structure–activity against Helicobacter pylori, and squalamine, a polyamine alkaloid from the dogfish shark that renders Mechanism of action Synergy Gram-negative pathogens 16- to >32-fold more susceptible to ciprofloxacin. Where available, informa- Antivirulence tion 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 colonisa- tion. The review concludes with implications and limitations of the described research and directions for future research. © 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. 1. Introduction of unknown aetiology [5,6]. Small-molecule drugs, for the time being, remain an essential component of infection treatment and Antibiotic resistance continues to rise and, with the emergence prevention. Two proven strategies within this paradigm are the of pan-resistant untreatable Enterobacteriaceae and Acinetobacter development of new drugs with direct antibacterial activity (e.g. spp., the dawn of the much forewarned post-antibiotic era has daptomycin) and adjuncts with antibiotic-enhancing activity (e.g. arguably broken [1]. Improved antibiotic stewardship should help tazobactam) [1]. A third, as yet clinically unproven strategy, is reduce the rate of future losses [2], but antibiotic lifespan is limited the development of drugs that disrupt bacterial pathogenesis even with careful use [3], so this does not negate the need for by inhibiting adhesins, autoinducers and other virulence factors new anti-infective medications. Biologicals can reduce our depend- [7]. ence on antibiotics and the selective pressure for resistance, but Historically, natural products have been a rich source of antibac- several limitations prevent them replacing antibacterial drugs. For terial drugs. Although the 1980s saw a decline in this type of example, safety and efficacy issues preclude vaccine use in severely research in favour of more readily manipulated synthetic com- immunocompromised patients [4], whilst narrow-spectrum activ- pound libraries, this trend is reversing. Synthetic chemical libraries, ity precludes monoclonal antibody and phage therapy in infections it is now recognised, tend to be limited in their structural diversity and a poor source of antibacterial leads [8]. Other factors driving renewed interest in natural products include the discovery of new ∗ prokaryotic and eukaryotic species in formerly unexplored envi- Corresponding author. Tel.: +66 43 754 32240x1159. E-mail address: t [email protected] (T.P.T. Cushnie). ronmental niches [9], technological advancements in separation, http://dx.doi.org/10.1016/j.ijantimicag.2014.06.001 0924-8579/© 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. 378 T.P.T. Cushnie et al. / International Journal of Antimicrobial Agents 44 (2014) 377–386 structure elucidation, dereplication, genome mining and combi- up to five. This nitrogen may occur in the form of a primary amine natorial biosynthesis [10,11], and, in the case of medicinal plants (RNH2), a secondary amine (R2NH) or a tertiary amine (R3N) [19]. In and other traditional medicines, concerns that potentially use- addition to carbon, hydrogen and nitrogen, most alkaloids contain ful medical knowledge and materials are being lost due to urban oxygen. Alkaloids can occur as monomers or they may form dimers expansion and species extinction [12]. Efforts to develop synthetic (also known as bisalkaloids), trimers or tetramers. Such oligomers antibacterial drugs have not been abandoned but are now more are typically homooligomers, but heterooligomers also occur focused on derivatization of natural molecules and synthesis of [14]. natural-product-like compounds using well-known natural prod- No single taxonomic principle exists that would allow con- uct scaffolds [13]. sistent classification of all alkaloids. Where possible, alkaloids Alkaloids are a large and structurally diverse group of natural are classified according to chemical structure, biochemical ori- products of microbial, plant and animal origin. Responsible for the gin and/or natural origin [14,18]. In terms of chemical structure, beneficial effects of traditional medicines such as cinchona bark, there are two broad divisions of alkaloids: the heterocyclic alka- but also the harmful effects of poisons such as ergot, they have a loids (also known as typical alkaloids) that contain nitrogen in reputation as both Nature’s curse and blessing [14]. Alkaloids have the heterocycle; and the non-heterocyclic alkaloids (also known inspired the development of several antibacterial drugs, with syn- as atypical alkaloids or protoalkaloids) that contain nitrogen in thesis of quinine serendipitously yielding the quinolones, structural a side chain [18]. Heterocyclic alkaloids are typically classified alteration of azomycin yielding metronidazole, and work with the according to their ring structure (Fig. 1a), although the structural quinoline scaffold yielding bedaquiline. In other drugs, alkaloids are complexity of these sometimes exceeds the number of subdivisions present as scaffold substructures, e.g. linezolid and trimethoprim. [37]. Non-heterocyclic alkaloids, by comparison, are often divided Alkaloids remain the focus of much research, their development according to biosynthetic origin. This is possible because their as antibacterial drugs pursued within academia, industry and joint amino acid precursors remain largely intact in the alkaloid struc- ventures [15–17]. This review seeks to integrate knowledge from ture [37]. Classification according to natural origin is also possible, the extensive and often widely scattered literature on antibac- since specific alkaloids are typically confined to specific sources terial alkaloids. Naturally occurring, semisynthetic and synthetic [18]. alkaloids are all included provided they are structurally novel Individual alkaloids are assigned names in various ways, but with chemotherapeutic or chemoprophylactic potential. Studies almost all names end with the letters ‘-ine’ [19]. Most alkaloids with well-characterised pharmacophores already in clinical trials are named after the organism or part of the organism from which or clinical use have been excluded, as have studies investigating they were isolated (e.g. atropine from Atropa belladonna) [18,19]. alkaloids as immunomodulators. Structural information on all the When multiple alkaloids are obtained from the same source, a pre- described alkaloids is presented in Supplementary Table S1. fix or more complicated suffix is used (e.g. quinine, hydroquinine, quinidine) or alternatively a series of letters (e.g. epicoccarine A, epicoccarine B) [19,38]. Alkaloids may also be named after the geo- 2. Occurrence, functions, structure, classification and graphic location of their source (e.g. tasmanine was isolated from nomenclature a Tasmanian plant) [14], their pharmacological activity (e.g. eme- tine induces vomiting) or, in some cases, after their discoverer (e.g. Alkaloids are found in bacteria, fungi, plants and animals, pelletierine after Prof. Pelletier) [19]. although their distribution within each kingdom is quite limited. They occur in ca. 300 plant families, specific compounds typically confined to certain families (e.g. hyoscyamine in Solanaceae) [18]. 3. Physiochemical, pharmacological and toxicological Alkaloids can occur in any part of the plant, though specific com- properties pounds may be limited to a certain part (e.g. quinine in cinchona tree bark) [19]. In terrestrial animals, alkaloids have been reported