Discovery of Novel Inhibitors of the NorA Multidrug Transporter of Staphylococcus aureus

Abstract

Four novel inhibitors of the NorA efflux pump of Staphylococcus aureus, discovered through a virtual screening process, are reported. The four compounds belong to different chemical classes and were tested for their in vitro ability to block the efflux of a well-known NorA substrate, as well as for their ability to potentiate the effect of ciprofloxacin (CPX) on several strains of S. aureus, including a NorA overexpressing strain. Additionally, the MIC values of each of the compounds individually are reported. A structure-activity relationship study was also performed on these novel chemotypes, revealing three new compounds that are also potent NorA inhibitors. The virtual screening procedure employed FLAP, a new methodology based on GRID force field descriptors.

Challenges and future prospects of antibiotic therapy: from peptides to phages utilization

“…Screening of efflux pump inhibitors from natural origins or under synthetic production has attracted remarkable attention (Hudson et al, 2003). Structural modifications of such compounds may lead to an increase in the spectrum of activities A wide number of effective chemical compounds belonging to various chemical families have already showed efflux pump inhibition (Brincat et al, 2011; Holler et al, 2012a, b). Moreover, some plant-derived NorA EPIs and their chemical modifications are carried out effectively (Thota et al, 2008; Sabatini et al, 2011; Kalia et al, 2012).…”

The Importance of Efflux Systems in Antibiotic Resistance and Efflux Pump Inhibitors in the Management of Resistance

“…Örneğin PAβN ve NMP gibi pompa inhibitörü bileşiklerin, dirençli gram-negatif bakterilerdeki siprofl oksasin MİK değerlerine etkisinin araştırıldığı çalışmalarda; PAβN'nin P.aeruginosa, E.coli ve A.baumannii klinik izolatlarında, NMP'nin ise E.coli ve K.pneumoniae klinik izolatlarında siprofl oksasin MİK değerlerinde belirgin azalmaya yol açtığı tespit edilmiştir 39,40 . Benzer şekilde, çeşitli antibiyotiklere dirençli bakteriler üzerinde çeşitli inhibitör bileşikler denenerek yapılmış pek çok araştırma vardır 6,41,42 .…”

“…İlk olarak, bakteri hücre membranının porin kaybına uğramasıyla geçirgenliği azalmakta ve böylelikle ilaç hücre içerisine yeterince girememektedir. Diğer mekanizmada ise, dışa atım pompalarının aşırı eksprese olması ve böylelikle etkin bir şekilde içerideki ilacı dışa-rıya atması söz konusudur [4][5][6][7] .…”

A Method for Determining 1,4-Benzothiazine Derivatives in Rat Plasma by HPLC and Its Application to a Pharmacokinetic Study

“…The 1,4-benzothiazine are molecules of enormous significance and consider as important targets because of their broad spectrum of biological activities [3]. Literature survey reveals that 1,4-benzothiazines exhibit wide pharmacological activities such as antagonists [6][7], anticancer [8], vasorelaxant [9], antidiabetic [10], antihypertensive [11], antimicrobial [12], analgesic [13], anti-HCV [14], antimalarial [15], antithyroid [16] and antitubercular [17].…”