Identifying the CmbT substrates specificity by using a quantitative structure-activity relationship (QSAR) study

Abstract

The CmbT substrate specificity and its role as a proton motive force-driven drug efflux pump at a molecular level were investigated in the study. In that order, 3D-quantitative structure-activity relationship (3D-QSAR) study was applied for selection of molecular determinants of multidrug recognition by CmbT. CmbT multidrug resistance protein of Lactococcus lactis contributes to extruding the structurally, chemically, and pharmacologically diverse range of substrates out of bacterial cells. This function of CmbT may result in the failure of antibiotic therapy. Homology model of CmbT protein was constructed and further opthnized. The 3D-QSAR model predictive potential was proved by use of leave-one-out cross validation Of the training set (Q(2): 0.69, R-observd(2) (vs).(Predicted) : 0.918, RMSEE: 0.193) and verification set (R-Observed vs predicted(2) : 0.704, RMSEP: 0.289). The results obtained in this study showed that high CmbT affinities to ethidium, sulbactam, and sulfathiazole could be related to the absence of significant unfavourable interactions. In contrast, the presence of specific unfavourable interaction between two hydrogen bond donor groups in bacitracin, apramycin, novobiocin, vancomycin, kanamycin, gentamycin, and tobramycin is found to be the main reason for their lower CmbT affinities. In addition, membrane position of the CmbT binding site and positive correlation between substrates lipophilicity (log D-PH so) and CmbT affinity strongly indicates that CmbT recognizes its substrates within the membrane.