Mini review
Cyclic lipopeptides as antibacterial agents – Potent antibiotic activity mediated by intriguing mode of actions

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Abstract

Cyclic lipopeptides (CLPs) are a promising class of natural products with antibiotic properties. CLPs are amphiphilic molecules, composed of a fatty acid tail linked to a short oligopeptide which form a macrocylic ring structure. This review presents an overview of this class of antibiotics, focusing on the current and potential therapeutic applications and placing particular emphasis on the molecular modes of action of these compounds.

Introduction

The continuous emergence and worldwide spread of multi-resistant human pathogenic bacteria, particularly in hospital settings, requires, in addition to improved therapeutic regimens, new antibacterial compounds. Among the underutilized antibiotic candidate groups, cyclic lipopeptides (CLPs) represent a promising class of natural products with potent antibacterial activity.

CLPs are composed of a lipid tail linked to a short oligopeptide which is cyclized to form a lactone or lactam ring either between two amino acids in the peptide chain or between an amino acid and an amino- or hydroxyl-group bearing fatty acid moiety. An immense structural diversity arises from differences in the length (C6-C18) and composition of the fatty acid moiety (β-OH groups, iso-, anteiso-methyl branched forms) and from variations in the number (2-25 AA), type (basic, acidic, aromatic, aliphatic, cyclic, OH/SH-containing, α- or β-type), and configuration (d, l) of the amino acids in the peptide portion. Particularly striking is the occurrence of unusually configured or modified proteinogenic amino acids or the incorporation of non-proteinogenic amino acids, a feature that makes CLPs less prone to ubiquitous peptidases. The presence of unusual amino acids is attributable to the fact that CLPs are biosynthesized by non-ribosomal pathways. Most natural CLPs are secondary metabolites of soil-borne or plant-associated bacteria of the genera Actinomyces, Streptomyces, Bacillus and Pseudomonas. Occasionally, eubacteria and cyanobacteria of marine origin are described as CLP-producers.

Cyclic lipopeptides have been subject of several recent reviews which cover aspects of their structural diversity and biological activities (Nielsen et al., 2002, Raaijmakers et al., 2006), biosynthesis (Kleinkauf and von Döhren, 1987, Roongsawang et al., 2011), fermentation (Shaligram and Singhal, 2010), regulation (Raaijmakers et al., 2006) and natural functions (Raaijmakers et al., 2010). In addition, reviews dealing specifically with synthetic or semi-synthetic CLPs have been reported (Jerala, 2007). Other authors highlighted the significance of CLPs as antibiotic agents (Singh and Cameotra, 2004, Hashizume and Nishimura, 2008, Pirri et al., 2009).

In this minireview we will first focus on the structural features and on the therapeutic applications of selected natural and semi-synthetic CLPs and subsequently provide an up-to-date overview of the current knowledge about their recently deciphered mode(s) of action. Due to space limitations this review only covers therapeutically significant CLPs or those which are in the antibiotic development pipeline.

Section snippets

Polymyxins

Polymyxins are a group of basic decalipopeptides with a remarkable content of the non-proteinogenic amino acid 2,4-diamino butyric acid (Storm et al., 1977). Generally, seven amino acids form a peptide cycle, and a fatty acid is fused to the C-terminus of the three exocyclic amino acids. 6-methyl-octanoic acid or 6-methyl-heptanoic acid can be found as lipid side chain moiety. Two representatives, polymyxin B (i.e. a mix of polymyxin B1 and B2) and E (i.e. a mix of polymyxin E1 and E2, syn.

Daptomycin

Daptomycin (originally designated LY146032) is one of the few antibiotics that were approved during the past decade and was successfully launched for the treatment of complicated skin and skin-structure infections, right-sided endocarditis and bacteremia caused by Gram-positive pathogens, including methicillin resistant Staphylococcus aureus (MRSA), vancomycin resistant Staphylococcus aureus (VRSA) and enterococci (VRE) (Johnson, 2006, Sauermann et al., 2008). Although being initially

Friulimicin, Amphomycin and derivatives

Amphomycin has first been described in the early 1950s and is produced as a secondary metabolite by Streptomyces canus ATCC 12237 (Heinemann et al., 1953). In the following years a series of structurally closely related peptides has been characterized, which can basically be divided into three families – the friulimicins, amphomycins and glycinocins (laspartomycins). The structural features common to these lipopeptides include the macrocyclic decapeptide core and a lipid tail, interlinked by

Empedopeptin, Tripropeptins and Plusbacins

The naturally occurring tripropeptins, plusbacins and empedopeptin share considerable structural similarity (Hashizume et al., 2004, Shoji et al., 1992, Sugawara et al., 1984). They define one type of guanidine-containing cyclic lipopeptides with a common structural scaffold, that contains arginine and two hydroxyaspartic acids. CLPs within this group differ only by variations in the first three amino acids, in the absolute configuration of Ser6 and in the fatty acid moieties attached, that can

WAP-8294A2 (Lotilibcin)

WAP-8294A is a complex mixture consisting of 19 closely related, water-soluble lipodepsipeptides produced by Gram-negative Lysobacter spec. (Harad et al., 2001, Kato et al., 1997, Kato et al., 1998). WAP-8294A2 (Lotilibcin), the major compound of this mixture exhibits potent antibacterial activity against Gram-positive bacteria, including MRSA and VRE. WAP-8294A2 is currently developed by aRigen and the Green Cross Cooperation for treatment of systemic MRSA infections and acne. The antibiotic

Ramoplanin

Ramoplanin is a lipoglycodepsipeptide antibiotic isolated from the fermentation broth of Actinoplanes sp. ATCC 33076 as a mixture of three closely related compounds, ramoplanin A1-A3 (Cavalleri et al., 1984), that basically differ in the structure of the fatty acid substituent. Members of the ramoplanin family all share an identical 17-mer peptide ring structure, composed of a number of unusual and β-hydroxylated amino acids (Fig. 6). Characteristically the l-hydroxyphenylglycine (Hpg) residue

Acyldepsipeptides (ADEPs)

In the 1980s researchers at Eli Lilly discovered a series of highly active antimicrobial hexa-lipopeptides, termed A54556 factors, which were produced by Streptomyces hawaiiensis NRRL 15010 (Michel and Kastner, 1985) (Fig. 7).

Two decades later, Bayer Healthcare reinvestigated A54556 factor A, established a chemical synthesis protocol and performed mode of action studies (Brötz-Oesterhelt et al., 2005). A detailed account of this class of compounds is given elsewhere in this special issue,

Conclusions

CLPs exhibit potent antibacterial activities towards several Gram-positive as well as Gram-negative bacteria. Three representatives of this compound class are already applied in the clinics, while several promising CLPs are under clinical investigation (see Table 1). Novel structural features and sometimes unprecedented molecular mechanisms make CLPs promising candidates for future drug development.

Acknowledgements

The authors gratefully acknowledge funding from the Deutsche Forschungsgemeinschaft (DFG), grants GR 2673/2-2 (H.G.) and SCHN 1284/1-2 (T.S.) within the ‘Research Unit FOR854 – Post-Genomic Strategies for New Antibiotic Drugs and Targets’ and the German Center for Infection Research (DZIF) (T.S.).

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