Put a Bow on It: Knotted Antibiotics Take Center Stage
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antibiotics Review Put a Bow on It: Knotted Antibiotics Take Center Stage Stephanie Tan , Gaelen Moore and Justin Nodwell * Department of Biochemistry, MaRS Discovery District, University of Toronto, 661 University Avenue, Toronto, ON M5G 1M1, Canada * Correspondence: [email protected]; Tel.: +1-416-946-8890 Received: 18 July 2019; Accepted: 9 August 2019; Published: 11 August 2019 Abstract: Ribosomally-synthesized and post-translationally modified peptides (RiPPs) are a large class of natural products produced across all domains of life. The lasso peptides, a subclass of RiPPs with a lasso-like structure, are structurally and functionally unique compared to other known peptide antibiotics in that the linear peptide is literally “tied in a knot” during its post-translational maturation. This underexplored class of peptides brings chemical diversity and unique modes of action to the antibiotic space. To date, eight different lasso peptides have been shown to target three known molecular machines: RNA polymerase, the lipid II precursor in peptidoglycan biosynthesis, and the ClpC1 subunit of the Clp protease involved in protein homeostasis. Here, we discuss the current knowledge on lasso peptide biosynthesis as well as their antibiotic activity, molecular targets, and mechanisms of action. Keywords: lasso peptides; ribosomally synthesized post translationally modified peptide (RiPP); antibiotic; target; mechanism of action 1. Introduction The natural products known as secondary or specialized metabolites are the source of thousands of antibiotics and other drugs that are critical for current medical practice. The majority of these compounds originated from the Actinobacteria, especially the streptomycetes, as well as lower fungi. The numbers of compounds produced by each species ranges from less than five in most cases to as many as 50 in the Actinobacteria and fungi. These compounds have a broad range of biological activities including many with therapeutic potential. However, many of the secondary metabolites encoded in the genome database remain unknown as their structures and biological activities have not yet been identified. Gaining access to this chemical space will provide us more resources to combat antimicrobial resistance and potential other areas of unmet medical need [1–4]. In addition, characterizing these molecules will shed light on poorly understood mechanisms and enzymes, a valuable goal on the road to new treatments for bacterial pathogens. Over 60% of the antimicrobials brought to market are natural products or derivatives thereof [5]. Peptide antibiotics are a subset of natural products and can be of ribosomal or non-ribosomal origin. While non-ribosomal peptide antibiotics such as the β-lactams and the glycopeptides are familiar, the ribosomally-synthesized and post-translationally modified peptides (RiPPs) are less well understood [6]. The RiPPs are a large class of chemically and functionally diverse peptides which includes members such as nisin, a food preservative, thiostrepton, an antibacterial used in veterinary medicine, and omega-conotoxin MVIIA, which has been developed into a synthetic analgesic drug [7–10]. The RiPP family contains impressive structural diversity, introduced by post-translational modifications, which gives this class of peptides a spectrum of activities ranging from antibacterial to morphogenic to analgesic. Antibiotics 2019, 8, 117; doi:10.3390/antibiotics8030117 www.mdpi.com/journal/antibiotics Antibiotics 2019, 8, 117 2 of 17 Antibiotics 2019, 8, x FOR PEER REVIEW 2 of 16 To ourour knowledge,knowledge, nonenone ofof thethe knownknown RiPPsRiPPs havehave foundfound clinicalclinical applicationapplication asas antimicrobialsantimicrobials at thisthis time;time; relativelyrelatively fewfew havehave foundfound anyany technicaltechnical applicationapplication atat allall outsideoutside thethe laboratory.laboratory. The lanthipeptidelanthipeptide nisinnisin is is an an exception: exception: it isit usedis used as a as food a food additive additive [11]. One[11].possible One possible road block road to block serious to considerationserious consideration of the RiPPs of the is RiPPs that, because is that, because of their largeof their size large (usually size (usually> 1.5 kDa), > 1.5 numerous kDa), numerous H-bond acceptorH-bond acceptor and donor and groups, donor and groups, other and properties, other properties, virtually none virtually of them none obey of them Lipinski’s obey ruleLipinski’s of five [rule12]. Weof five argue [12]. that We this argue departure that this from depa conventionrture from isconvention part of what is part is so of attractive what is so about attractive these about molecules: these theymolecules: fall well they outside fall well of theoutside known of antibioticthe known chemical antibiotic space. chemical Indeed, space. the In verydeed, successful the very antibioticssuccessful vancomycinantibiotics vancomycin and daptomycin and daptomycin also disobey also the ruledisobey of five the and rule there of five have and been there many have arguments been many that thesearguments rules arethat too these restrictive rules are for too antibiotic restrictive discovery for antibiotic [13]. As wediscovery will show, [13]. while As we many will RiPPs show, interact while withmany well-known RiPPs interact antibiotic with well-kno targets,wn others antibiotic target noveltargets, pathways. others target At the novel very pathways. least therefore, At the thesevery moleculesleast therefore, are powerful these molecules chemical are probes powerful pointing chemic to newal probes biology pointing that can beto new targeted biology for antibacterial that can be therapy.targeted Wefor wouldantibacterial go one therapy. step further We would by predicting go one thatstep there further will by eventually predicting be that RiPPs there or RiPPwill derivativeseventually be in RiPPs clinical or use. RiPP derivatives in clinical use. While the RiPPsRiPPs areare structurallystructurally andand functionallyfunctionally diverse,diverse, the family contains a unifyingunifying biosynthetic logic. logic. All All RiPPs RiPPs are are genomically genomically encode encodedd as a asprecursor a precursor peptide peptide which which consists consists of an N- of anterminal N-terminal (or occasionally (or occasionally C-terminal) C-terminal) leader leader sequen sequencece and a and C-terminal a C-terminal core sequence core sequence (Figure (Figure 1). The1). Theleader leader sequence sequence enables enables the recognition the recognition of the of RiPP the RiPPprecursor precursor by the by enzymes the enzymes that perform that perform post- post-translationaltranslational modifications modifications in the in C-terminal the C-terminal core. core.The mature The mature RiPP RiPPis produced is produced when whenthe post- the post-translationaltranslational modifications modifications of the of C-terminal the C-terminal sequen sequencece are arecomplete complete and and the the N-terminal N-terminal sequence sequence is iscleaved cleaved off. o ffSome. Some RiPP RiPP gene gene clusters clusters encode encode dedica dedicatedted transport transport and and regulation regulation genes genes [6]. [Using6]. Using this thisstrategy, strategy, the theRiPPs RiPPs natural natural products products achieve achieve impressive impressive chemical chemical and and functional functional diversity. diversity. While others havehave reviewedreviewed thethe variousvarious sub-families sub-families of of RiPPs RiPPs [14 [14–16],–16], in in this this review review we we will will focus focus on on one one of theof the newest newest sub-families sub-families of RiPPs,of RiPPs, the the lasso lasso peptides. peptides. Figure 1. BiosynthesisBiosynthesis of of ribosomally-synthesized ribosomally-synthesized and and post-translationally post-translationally modified modified peptides peptides (RiPPs). (RiPPs). ((A)) GeneralGeneral overviewoverview ofof RiPPRiPP biosyntheticbiosynthetic genegene clusters.clusters. (B) Processing of the precursor peptide into thethe maturemature RiPP.RiPP. 2. Lasso Peptides The lasso peptidespeptides are aa largelarge familyfamily ofof chemicallychemically diversediverse andand poorlypoorly understoodunderstood RiPPs.RiPPs. The firstfirst member of this family, anantin,anantin, waswas identifiedidentified lessless thanthan 3030 yearsyears agoago [[17].17]. LassoLasso peptidespeptides rangerange from 14 to to 24 24 amino amino acid acid residues residues in in length length and and contain contain a characteristic a characteristic isopeptide isopeptide bond bond between between the theN-terminal N-terminal amine amine and andthe thecarboxy carboxy group group of a ofglutamate a glutamate or aspartate or aspartate residue residue in the in the7th, 7th,8th, 8th,or 9th or 9thposition position (Figure (Figure 2B)-this2B)-this creates creates an an N-terminal N-terminal ma macrocyclecrocycle [18]. [ 18 ].The The C-terminal C-terminal tail tail is threadedthreaded through thethe N-terminalN-terminal macrocycle,macrocycle, producingproducing aa topologytopology whichwhich resemblesresembles aa lasso.lasso. In somesome lassolasso peptides, large, bulky bulky amino amino acids acids act act as as “steric “steric plugs” plugs” to toprevent prevent unthreading unthreading of the of theC-terminal C-terminal tail tailfrom from the theN-terminal N-terminal macrocycle. macrocycle. This This lasso lasso topolo topologygy provides provides stability stability and and as as a a result, result,