Antibiyotik Direncinde Dışa Atım Sistemlerinin ve Dirençle Mücadelede Dışa Atım Pompa İnhibitörlerinin Önemi
Küçük Resim Yok
Tarih
2015
Yazarlar
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
En son tanımlanan direnç mekanizması olan aktif dışa atım (effl ux) olayı, bakterilerde kazanılmış antibiyotik direncinin önemli nedenlerinden birisidir. Ökaryotik ve prokaryotik tüm hücre tiplerinde bulunan, hücre membranına yerleşmiş pompa proteinleri olan dışa atım sistemleri, ekzojen ve endojen kaynaklı çeşitli maddelerin hücre dışına atımından sorumludur. Bakteriyel pompa proteinleri; ATP Binding Cassette (ABC), Major Facilitator (MFS), Multidrug and Toxic Compound Extrusion (MATE), Resistance - Nodulation - Division (RND) ve Small Multidrug Resistance (SMR) olmak üzere beş süper aile içerisinde gruplandırılmıştır. Dışa atım pompaları bazı patojenlerde antibiyotiklere karşı doğal dirençte rol oynarlar. Bu pompalar ayrıca, aşırı eksprese olarak ve diğer direnç mekanizmalarına katkı sağlayarak kazanılmış dirence neden olurlar. Dahası, dışa atım pompaları doğrudan veya dolaylı yollarla bakterilerin virülans özelliklerini kuvvetlendirebilirler. Dolayısıyla, dışa atım kaynaklı direncin önüne geçilebilmesi veya dirençli bakterilerin yeniden duyarlı hale getirilebilmesi için, geleneksel antibiyotiklerle kombine edilerek kullanı- ma sunulabilecek potansiyel pompa inhibitörleri, dirençle mücadelede ilgi çekici araştırma alanlarından birisidir. Bakteriyel pompa sistemlerini inhibe ettiği bilinen bazı bileşiklere örnek olarak; fenil-arjinin betanaftilamid (PA?N), INF271, INF55, karbonil siyanid m-klorofenil hidrazon (CCCP), rezerpin, 1-(1-naftilmetil) piperazin (NMP), birikodar, timkodar, verapamil, milbemisin, klorpromazin, paroksetin ve omeprazol verilebilir. Ancak özellikle toksisite problemlerinden dolayı, henüz klinik kullanımı olan bir pompa inhibitörü yoktur. Buna rağmen, dışa atım pompa inhibitörlerinin toksisitesi kabul edilebilir düzeyde olan etkili türevleri, önümüzdeki dönemlerde antibakteriyel formülasyonlara girebilir. Ayrıca endüstriyel ve akademik alanda faaliyet yürüten pek çok araştırmacı tarafından, pompa inhibisyonu özelliği keşfedilen doğal ve sentetik kaynaklı pek çok bileşik rapor edilmektedir. Bu çerçevede, patent başvuru örnekleri de olan çeşitli antibiyotik türevi (tetrasiklin, aminoglikozit ve fl orokinolon analogları) ve antibiyotik dışı bileşikler (indol, üre, aromatik asit, piperidin-karboksilik asit, kinolin türevleri ve peptidomimetikler) sıklıkla çalışılmaktadır. Yapılan çalışmalarla, pompa inhibitörlerinin bazı antibiyotiklerin minimum inhibisyon konsantrasyonu (MİK) değerlerini düşürdüğü gösterilmiştir. Bu derleme yazıda, bakterilerdeki dışa atım pompalarının yapıları ve işlevleri özetlenmiş, doğal ve sentetik kaynaklı dışa atım pompa inhibitörleri genel anlamda değerlendirilmiştir.
The process of active effl ux, the last described resistance mechanism in bacteria, is one of the important factors of acquired antibiotic resistance. Effl ux systems which consist of membrane-located pump proteins that exist in all eukaryotic and prokaryotic cells, are responsible for extrusion of the various exogenous and endogenous substances. Bacterial pump proteins, namely ATP Binding Cassette (ABC), Major Facilitator (MFS), Small Multidrug Resistance (SMR), Multidrug and Toxic Compound Extrusion (MATE) and Resistance - Nodulation - Division (RND) are grouped in fi ve super families. Effl ux pumps play a role in intrinsic resistance against antibiotics among some pathogens. Besides, pumps give rise to acquired resistance by over-expression and contribute to other resistance mechanisms. Furthermore, pumps can directly or indirectly intensify the virulence properties of bacteria. Thus, for inhibition of effl ux-mediated resistance or conversion of resistant bacteria to the susceptible phenotype, potential pump inhibitors combined with traditional antibiotics is one of the research areas of interest in the fi ght against resistance. There are some compounds known to inhibit bacterial pump systems, such as phenyl-arginine beta naphthylamide (PAβN), INF271, INF55, carbonyl cyanide m-chlorophenyl hydrazone (CCCP), reserpine, 1-(1-naphthylmethyl)-piperazine (NMP), biricodar, timcodar, verapamil, milbemycin, chlorpromazine, paroxetine and omeprazole. However, particularly due to the toxicity problems, there has been no clinical use of a pump inhibitor yet. Nevertheless, in the upcoming period, derivatives of effl ux pump inhibitor compounds with acceptable level of toxicity and effi cacy may be included in antibacterial formulations. Additionally, a number of natural and synthetic compounds with pump inhibition activity are reported by many researchers in industrial and academic areas. In this context, various antibiotic derivatives (tetracycline, fl uoroquinolone and aminoglycoside analogs) or non-antibiotic compounds (indole, urea, aromatic acid, piperidine-carboxylic acid, quinoline derivatives and peptidomimetics), some of which already have patent applications, are often studied. Pump inhibitors are shown to reduce the minimum inhibitory concentration (MIC) values of various antibiotics in some studies. In this review article, the structure and functions of bacterial effl ux pumps have been summarized and the effl ux pump inhibitors with natural and synthetic origins have been evaluated.
The process of active effl ux, the last described resistance mechanism in bacteria, is one of the important factors of acquired antibiotic resistance. Effl ux systems which consist of membrane-located pump proteins that exist in all eukaryotic and prokaryotic cells, are responsible for extrusion of the various exogenous and endogenous substances. Bacterial pump proteins, namely ATP Binding Cassette (ABC), Major Facilitator (MFS), Small Multidrug Resistance (SMR), Multidrug and Toxic Compound Extrusion (MATE) and Resistance - Nodulation - Division (RND) are grouped in fi ve super families. Effl ux pumps play a role in intrinsic resistance against antibiotics among some pathogens. Besides, pumps give rise to acquired resistance by over-expression and contribute to other resistance mechanisms. Furthermore, pumps can directly or indirectly intensify the virulence properties of bacteria. Thus, for inhibition of effl ux-mediated resistance or conversion of resistant bacteria to the susceptible phenotype, potential pump inhibitors combined with traditional antibiotics is one of the research areas of interest in the fi ght against resistance. There are some compounds known to inhibit bacterial pump systems, such as phenyl-arginine beta naphthylamide (PAβN), INF271, INF55, carbonyl cyanide m-chlorophenyl hydrazone (CCCP), reserpine, 1-(1-naphthylmethyl)-piperazine (NMP), biricodar, timcodar, verapamil, milbemycin, chlorpromazine, paroxetine and omeprazole. However, particularly due to the toxicity problems, there has been no clinical use of a pump inhibitor yet. Nevertheless, in the upcoming period, derivatives of effl ux pump inhibitor compounds with acceptable level of toxicity and effi cacy may be included in antibacterial formulations. Additionally, a number of natural and synthetic compounds with pump inhibition activity are reported by many researchers in industrial and academic areas. In this context, various antibiotic derivatives (tetracycline, fl uoroquinolone and aminoglycoside analogs) or non-antibiotic compounds (indole, urea, aromatic acid, piperidine-carboxylic acid, quinoline derivatives and peptidomimetics), some of which already have patent applications, are often studied. Pump inhibitors are shown to reduce the minimum inhibitory concentration (MIC) values of various antibiotics in some studies. In this review article, the structure and functions of bacterial effl ux pumps have been summarized and the effl ux pump inhibitors with natural and synthetic origins have been evaluated.
Açıklama
Anahtar Kelimeler
Mikrobiyoloji
Kaynak
Mikrobiyoloji Bülteni
WoS Q Değeri
Scopus Q Değeri
Cilt
49
Sayı
2
