M. M. C. Ferreira, R. Kiralj, "QSAR Study of b-Lactam Antibiotic Efflux by the Bacterial Multidrug Resistance Pump AcrB". Rio de Janeiro, RJ, Brazil, 22-25/11/2004: The 2nd Brazilian Symposium on Medicinal Chemistry: Current Trends in Drug Discovery and Development. Abstract Book, (2004) 76. Poster S3-132. Session 3 (S3): Drug Design: Tools in Chemo- and Bioinformatics.

Key words: AcrB multidrug resistance efflux pump, b-lactam antibiotics, Quantitative Structure-Activity Relationship (QSAR)
Principal Component (PCA) and Hierarchical Cluster (HCA) Analysis and Partial Least Squares (PLS) regression have been  applied  in the QSAR study  of  16  b-lactam antibiotics  (penicillins and cephalosporins)  as  substrates  of  multidrug  resistance efflux  membrane
pump AcrAB-TolC in three strains of Salmonella typhimurium. Electronic and hydrogen bonding molecular descriptors  were  obtained
by  using  quantum chemical  methods  or  structure  fragment  counts,   while  lipophilicity  descriptors  were  generated  using  various
calculation methods.   PCA - HCA analysis  on three activity scales (pMICs) resulted in classification of  samples  as good,   moderately
good and poor pump substrates,   and in clear evidence that the efflux activity  is  determined also  by  bacterial strain.   The  analogous analysis on lipophilicity descriptors discovered significant differences among them and clustering of samples in accordance with the type of  b-lactam  side  chains.   The parsimonius  cross-validated  PLS  models  with  three principal components   (Q=0.86-0.98,  R=0.94-
0.99, SEP=0.21-0.46)  included   linear  and  non-linear  terms  of  some  lipophilicity  descriptors,   hydrogen  bonding  and  electronic
descriptors  related  to  drug  amphiphilicity.
 
 

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