Publication: Investigation of oxa enzyme inhibitors using computational tools
Abstract
Son yıllarda farklı bakteri türlerinin geliştirdiği antibiyotik dirençlerine bağlı olarak artan hastane enfeksiyonu vakaları endişe vericidir. Pseudomonas aeruginosa, Acinetobacter. baumannii, K. pneumoniae ve Enterobacteriaceae türleri, hayati hücresel fonksiyonları için metabolizmalarında sentezledikleri farklı β-laktamaz sınıfları aracılığıyla gerek geleneksel gerekse yeni nesil β-laktamlara karşı direnç mekanizmaları geliştirmektedir. Bunlar arasında CDBL, diğer tüm sınıflar içinde endişe verici olanlardır. Bugüne kadar amino asit dizilimleri farklı olsa da benzer 3D yapılara sahip 950'den fazla CDBL yapısı tanımlanmıştır. Yapısal benzerliklerinin aksine, CDBL'ler hem kendi içlerinde hem de A sınıfı β-laktamazlarla karşılaştırıldıklarında antibiyotiklere karşı farklı hidrolitik aktivitelere ve etkinliklere sahiptir. CDBL'ler arasında OXA10, OXA23 ve OXA48, 3D yapıları, fonksiyonel mekanizmaları ve substrat profilleri gibi hem benzer hem de farklı özellikler içermektedir. Bu çalışmada, üç farklı OXA enzim türüne karşı FDA onaylı doğal inhibitörlerin sanal kütüphane taraması yoluyla keşfedilmesi önerilmiştir. OXA10, OXA23 ve OXA48'in ilaç bağlanma mekanizmalarının araştırılması için moleküler yerleştirme ve MD simülasyonları gerçekleştirilmiştir. Seftriakson, kromolin, irinotekan ve PGA'nın her bir enzim için etkili inhibitörler olduğu bulunmuştur.
Increasing amount of nosocomial infectious cases due to the antibiotic resistances developed by different bacterial species is alarming in recent years. Pseudomonas aeruginosa, Acinetobacter. baumannii, Klebsiella. pneumoniae and Enterobacteriaceae species account for the development of resistive mechanisms against either conventional or new generation β-lactams through different classes of β-lactamases they synthesize in their metabolism for vital cellular functions. Among them, CDBL are alarming ones within all other classes. More than 950 CDBL structures have been identified up to date having similar 3D structures albeit varying amino acid sequences. In contrast to their structural similarities, CDBL different hydrolytic activities and efficiencies against antibiotics when compared either within themselves or with class A β-lactamases. Among CDBL, OXA10, OXA23 and OXA48 consist of both similar and varying properties such as their 3D structures, functional mechanisms, and substrate profiles. In this study, FDA approved natural inhibitors against the three different types of OXA enzymes were aimed to be discovered through virtual library screening. Molecular docking and MD simulations were performed for the investigation of drug binding mechanisms of OXA10, OXA23 and OXA48. Ceftriaxone, cromolyn, irinotecan and PGA were found to be effective inhibitors for each enzyme.
Increasing amount of nosocomial infectious cases due to the antibiotic resistances developed by different bacterial species is alarming in recent years. Pseudomonas aeruginosa, Acinetobacter. baumannii, Klebsiella. pneumoniae and Enterobacteriaceae species account for the development of resistive mechanisms against either conventional or new generation β-lactams through different classes of β-lactamases they synthesize in their metabolism for vital cellular functions. Among them, CDBL are alarming ones within all other classes. More than 950 CDBL structures have been identified up to date having similar 3D structures albeit varying amino acid sequences. In contrast to their structural similarities, CDBL different hydrolytic activities and efficiencies against antibiotics when compared either within themselves or with class A β-lactamases. Among CDBL, OXA10, OXA23 and OXA48 consist of both similar and varying properties such as their 3D structures, functional mechanisms, and substrate profiles. In this study, FDA approved natural inhibitors against the three different types of OXA enzymes were aimed to be discovered through virtual library screening. Molecular docking and MD simulations were performed for the investigation of drug binding mechanisms of OXA10, OXA23 and OXA48. Ceftriaxone, cromolyn, irinotecan and PGA were found to be effective inhibitors for each enzyme.