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Than a Pore: a Current Perspective on the in Vivo Mode of Action of the Lipopeptide Antibiotic Daptomycin

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Than a Pore: a Current Perspective on the in Vivo Mode of Action of the Lipopeptide Antibiotic Daptomycin antibiotics Review More Than a Pore: A Current Perspective on the In Vivo Mode of Action of the Lipopeptide Antibiotic Daptomycin Declan Alan Gray 1 and Michaela Wenzel 2,* 1 Newcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; [email protected] 2 Division of Chemical Biology, Department of Biology and Biological Engineering, Chalmers University of Technology, 412 96 Gothenburg, Sweden * Correspondence: [email protected]; Tel.: +46-31-772-2074 Received: 17 December 2019; Accepted: 31 December 2019; Published: 3 January 2020 Abstract: Daptomycin is a cyclic lipopeptide antibiotic, which was discovered in 1987 and entered the market in 2003. To date, it serves as last resort antibiotic to treat complicated skin infections, bacteremia, and right-sided endocarditis caused by Gram-positive pathogens, most prominently methicillin-resistant Staphylococcus aureus. Daptomycin was the last representative of a novel antibiotic class that was introduced to the clinic. It is also one of the few membrane-active compounds that can be applied systemically. While membrane-active antibiotics have long been limited to topical applications and were generally excluded from systemic drug development, they promise slower resistance development than many classical drugs that target single proteins. The success of daptomycin together with the emergence of more and more multi-resistant superbugs attracted renewed interest in this compound class. Studying daptomycin as a pioneering systemic membrane-active compound might help to pave the way for future membrane-targeting antibiotics. However, more than 30 years after its discovery, the exact mechanism of action of daptomycin is still debated. In particular, there is a prominent discrepancy between in vivo and in vitro studies. In this review, we discuss the current knowledge on the mechanism of daptomycin against Gram-positive bacteria and try to offer explanations for these conflicting observations. Keywords: daptomycin; lipopeptide antibiotic; mechanism of action; membrane domains; membrane fluidity 1. Introduction Daptomycin is a calcium-dependent cyclic lipopeptide, which was originally isolated in the 1980s from the Gram-positive soil actinomycete Streptomyces roseosporus. It was the first in class of a novel group of calcium-dependent, membrane-binding lipopeptides and was found to have impressive activity against Gram-positive, but not Gram-negative organisms [1,2]. Clinical studies were undertaken, however, it was found that high-dose treatment resulted in adverse effects, specifically myopathy [3], and as a result the antibiotic was shelved. Due to the drastic increase of antibiotic-resistant bacteria and the lack of sufficient novel antibiotic candidates daptomycin was revisited. Its side effects could be minimized through altering the dose regimen and it finally went on to receive approval from the U.S. food and drug administration (FDA) in 2003 [4]. Until the present day, the commercialization of daptomycin marks the last time that a new antibiotic class was introduced to the market. Since daptomycin is active against antibiotic-resistant bacteria and to preserve the last effective antibiotics at disposal in the clinic, it was classified as a last resort antibiotic along with vancomycin and Antibiotics 2020, 9, 17; doi:10.3390/antibiotics9010017 www.mdpi.com/journal/antibiotics Antibiotics 2020, 9, 17 2 of 21 Antibiotics 2020, 9, x 2 of 21 linezolid.[5]. Daptomycin Daptomycin is used is oneto treat of the skin few infections peptide, antibiotics bacteremia, that and can right-sided be administered endocarditis systemically caused [ 5by]. DaptomycinGram-positive is usedbacteria, to treatsuch skinas Staphylococcus infections, bacteremia, aureus, both and methicillin-susceptible right-sided endocarditis and caused -resistant by Gram-positive(MSSA and MRSA), bacteria, as suchwell as Staphylococcusseveral Streptococcus aureus, both and methicillin-susceptibleEnterococcus species [5]. and Several -resistant more (MSSA cyclic andlipopeptide MRSA),as antibiotics well as several haveStreptococcus been discovered,and Enterococcus but apart speciesfrom the [5]. polymyxins Several more and cyclic the lipopeptide antifungal antibioticsechinocandins, have daptomycin been discovered, is the but only apart one fromto currently the polymyxins have clinical and approval the antifungal [6]. echinocandins, daptomycinMembrane-active is the only oneantibiotics to currently hold havegreat clinical promise approval for slower [6]. resistance development and have recentlyMembrane-active attracted renewed antibiotics interest hold for great drug promise development for slower [7,8]. resistance Daptomycin development is the andonly have systemically recently attractedapplied renewedmembrane-active interest for antibiotic drug development that is available [7,8]. Daptomycin for treatment is the of only Gram-positive systemically bacterial applied membrane-activeinfections. Together antibiotic with that the is availableanti-Gram-negative for treatment ofpolymyxins Gram-positive and bacterial antifungal infections. peptides Together like withamphotericin the anti-Gram-negative B, daptomycin polymyxins pioneered the and systemic antifungal application peptides of like membrane-active amphotericin B, anti-infectives. daptomycin pioneeredLearning thefrom systemic its successes application and oflimitations membrane-active will help anti-infectives. to pave the Learningway for the from next its successesgeneration and of limitationspromising will antimicrobial help to pave drugs. the way However, for the next despite generation being of promisingwell-established antimicrobial in the drugs.clinic, However, its exact despitemechanism being is well-established still debated. inIntr theiguingly, clinic, itsthere exact appears mechanism to be is a still crucial debated. difference Intriguingly, between there its appearsmechanism to be of a crucial action differencein model memb betweenrane its systems mechanism and of living action bacterial in model ce membranells. In this systemsreview we and discuss living bacterialthe current cells. knowledge In this review on wethe discussmechanism the current of daptom knowledgeycin against on the mechanismGram-positive of daptomycin bacteria and against try to Gram-positiveexplain the apparent bacteria in and vivo try– toin explainvitro discrepancy the apparent in inits vivo–inbehavior. vitro discrepancy in its behavior. 2.2. StructureStructure and and Oligomerization Oligomerization of of Daptomycin Daptomycin DaptomycinDaptomycin isis composedcomposed of 13 13 amino amino acids, acids, 10 10 of of which which are are arranged arranged in a in cyclic a cyclic structure. structure. The Theexocyclic exocyclic tryptophan tryptophan at position at position 1 carries 1 carries a decanoyl a decanoyl fatty fattyacid tail acid (Figure tail (Figure 1) [9,10].1)[ 9The,10]. cyclic The cyclicregion regionof daptomycin of daptomycin contains contains several several noncanonical noncanonical and andD-amino D-amino acids acids (kynurenine, (kynurenine, ornithine, ornithine, 3- 3-methylglutamicmethylglutamic acid, acid, D-alanine, D-alanine, D-serine) D-serine) [2]. [2]. Kynurenine and 3-methylglutamic3-methylglutamic acidacid havehave beenbeen shownshown toto bebe crucial crucial for for daptomycin daptomycin activity. activity. PeptidesPeptides carryingcarrying modificationsmodifications atat thesethese positionspositions exhibitexhibit up up to to five five times times higher higher minimal minimal inhibitory inhibitory concentrations concentrations (MICs) (MICs) compared compared to to unmodified unmodified daptomycindaptomycin [11 [11].]. Another Another essential essential structural structural feature feature appears appears to be the to ester be bondthe ester between bond kynurenine between andkynurenine threonine and [12 ].threonine Acidic residues [12]. Acidic are conserved residues in are other conserved calcium-dependent in other calcium-dependent cyclic lipopeptides, cyclic for examplelipopeptides, friulimicin for example B and amphomycin friulimicin B A, and emphasizing amphomycin that complexA, emphasizing formation that with complex calcium formation and the resultingwith calcium charge and neutralization the resulting arecharge essential neutralization features of are this essential antibiotic features class [of13 ].this antibiotic class [13]. Figure 1. Structure of daptomycin. (A) Chemical structure. (B) Amino acid sequence. Dec: decanoyl Figure 1. Structure of daptomycin. (A) Chemical structure. (B) Amino acid sequence. Dec: decanoyl chain, L-Orn: L-ornithine, L-MeOGlu: L-methylglutamic acid, L-Kyn: L-kynurenine. chain, L-Orn: L-ornithine, L-MeOGlu: L-methylglutamic acid, L-Kyn: L-kynurenine. Antibiotics 2020, 9, 17 3 of 21 In contrast to other common lipopeptides like surfactin, polymyxins, or echinocandins, daptomycin has a negative net charge of 3 at pH 7 [14]. Its activity depends on the presence of Ca2+ ions, which − reduce the negative charge of the peptide head groups and stimulate oligomerization of daptomycin [15– 18]. The resulting daptomycin–calcium complex has a neutral net charge (2:3 daptomycin/Ca2+)[19]. Circular dichroism spectroscopy indicated that upon binding of calcium ions, daptomycin undergoes a structural transition that increases its amphipathicity [18]. NMR studies have suggested that the presence of calcium ions triggers the formation of daptomycin micelles, which are believed to facilitate its interaction
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