YENİ BİR GRUP ANTİMİKROBİYAL AJAN: SERAGENİNLER (KATYONİK STEROİD ANTİBİYOTİKLER)

Günümüzde özellikle Gram negatif ve Gram pozitif patojenler başta olmak üzere mikroorganizmalardaki çoklu ilaç direncinin artması, araştırmacıları alternatif tedavi seçeneklerinin ve antimikrobik etkili ajanların arayışına yöneltmiştir. Bu konuda sıklıkla çalışılan hedeflerden bir tanesi bakteri membranıdır. Bakteri membranını etkileyen birçok ajan, katyonik ve yüzeysel olarak amfifilik özellikte olup, LL-37 ve magainin gibi endojen antimikrobiyal peptidleri (AMP) de içeren moleküllerdir. Ancak, karmaşık yapı ve boyutlarından dolayı birçok AMP'nin sentezlenmesi ve saflaştırılması zordur. Bunlara ek olarak, AMP'ler proteazların substratları olabilmektedir ve bu da vücuttaki yarı ömürlerini etkilemektedir. AMP'lerin peptid olmayan formlarının geliştirilmesi, uzun zamandır kullanılan antimikrobiyal stratejilerinin ve peptid tedavilerin dezavantajları olmadan kullanılmasını sağlayacaktır. Son zamanlarda, bir dizi katyonik kolik asit türevi sentezlenmiş ve antimikrobiyal ajan olarak kullanılmalarını sağlayacak özellikleri saptanmıştır. AMP'leri taklit etmek üzere tasarlanan serageninler (Cationic Steroid Antibiotics-CSA-katyonik steroid antibiyotikler) toksisitesi düşük olan yeni bir sınıf antimikrobiyal moleküllerdir. Peptid yapıda olmayan serageninler tuza duyarlı değillerdir, büyük ölçeklerde hazırlanabilirler ve saflaştırılmaları nispeten daha kolaydır. Bunlardan biri olan CSA-13 (Cationic Steroid Antibiotic-13), prototip ceregenin molekülüdür ve dirençli suşlar dahil olmak üzere Gram pozitif ve Gram negatif bakterilere karşı oldukça etkilidir. CSA-13, vankomisine dirençli Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii ve Helicobacter pylori gibi bakterilere ek olarak; Streptococcus mutans ve Porphyromonas türleri gibi periodontopatik bakterilere karşı antimikrobiyal özellik göstermektedir. Serageninlerin sahip olduğu antibakteriyal etkilerinin yanı sıra, bu moleküller aynı zamanda, antifungal, antiviral, antiparazitik, antibiyofilm ve antikanser etki de gösterebilmektedirler. CSA'ların tüm hücresel aktiviteleri bakterilerin plazma membranı ile ilişkili olup, membran içine girdikten sonra etkilerini membranın depolarizasyonu ile sonuçlanan birtakım membran organizasyonu değişiklikleri ile göstermektedir. Ancak, serageninlerin stabilite, immünogenetik, farmakokinetik ve farmakodinamik özelliklerindeki eksiklikler, bu konuda daha fazla araştırma yapılmasını gerektirmektedir. Bu derlemede, bu ajanların çeşitli özelliklerinin tartışılıp, aktiviteleri hakkında şu anakadar bilinenlerin ve mikrobiyal özgüllüklerinin incelenmesi amaçlanmıştır

A Novel Class of Antimicrobial Agents: Ceragenins (Cationic Steroid Antibiotics)

A Novel Class of Antimicrobial Agents: Ceragenins (Cationic Steroid Antibiotics)The emergence of multidrug resistance in microorganisms, especially in Gram negative and Gram positive pathogens led the researchers to search for alternative therapeutic options and antimicrobial agents. One frequently studied target is the bacterial membrane. Many agents that target the bacterial membrane are cationic, facially amphiphilic molecules including endogenous antimicrobial peptides (AMP) like LL-37 and magainin. However, many AMPs are difficult to synthesize and purify due to their complexity and size. In addition, AMPs can be substrates for proteases, which limit their in vivo half-lives. Consequently, development of nonpeptide mimics of AMPs may provide a means of using the antimicrobial strategies evolved over eons without the disadvantages of peptide therapeutics. Recently, a series of cationic derivatives of cholic acid have been synthesized and have been found to have properties that may make them useful antimicrobial agents. Ceragenins, (Cationic Steroid Antibiotics-CSA) designed to mimic the activities of AMPs, are a new class of antimicrobial agent those have low toxicity. Ceragenins are not peptide based, they are not salt sensitive, and they are relatively simple to prepare and purify on a large scale. Among them, CSA-13, which stands for cationic steroid antibiotics, is a lead ceragenin and is highly active against Gram positive and Gram negative bacteria including resistant strains. CSA-13 displays antimicrobial activity against vancomycin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii, Helicobacter pylori, and periodontopathic bacteria such as Streptococcus mutans and Porphyromonas species. As well as their antibacterial activities, these molecules also can show antifungal, antiviral, antiparasitic, antibiofilm and anticancer effects. All cellular activities of CSA involve interactions with plasma membranes, and the mechanism of bacterial cell killing is associated with changes in membrane organization after CSA insertion into the plasma membrane, which results in membrane depolarization. However, major concerns surrounding ceragenins such as stability, immunogenity, pharmacokinetic and pharmacodynamic parameters are needed further investigation. In the present review we will discuss the properties of these agents and what is currently known about their mode of action and microbial specificity

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