Research Article
Shazi Shakil and Asad Ullah Kh
Abstract
Extended-spectrum- β -lactamases (ESBLs) are enzymes produced by bacteria which impart resistance against advanced-generation-cephalosporins. CTX-M enzymes have become the most prevalent ESBLs. The amino acid residues through which 2009 CTX-M-variants interact with drugs and inhibitors is not reported. Homology models for CTX-M-15 (This study), CTX-M-53, CTX-M-71, CTX-M-82 and CTX-M-89 were prepared. Ramachandran-Z-scores for models were found to be -0.449, 0.006, -0.103, -0.007 and 0.092, respectively. These models were docked with target drugs (cefotaxime, ceftazidime, cefepime) and inhibitors (clavulanate, sulbactam, tazobactam). The bla CTX-M-15 marker was PCR-ampli fi ed from plasmid DNA of clinical Escherichia coli isolate. Minimum inhibitory concentrations (MICs) for drugs were tested by the microbroth-dilution-method. E. coli C600 cells (harboring cloned bla CTX-M-15 ) were found positive for ESBL-production by the double-disk-synergy test. The bla CTX-M-15 marker was found transmissible through conjugation. Discovery Studio analysis of the docked structures revealed that irrespective of the CTX-M-type, ceftazidime interacted with the residues A226, G227, L228, P229, A/T230, S231, W232, R285, T288, D289, G290 and L/Y291. Moreover, sulbactam was found to bind most ef fi ciently to the studied enzymes on the basis of interaction energies. The study identi fi es amino acid residues crucial to ‘CTX-M-drug’ and ‘CTX-M-inhibitor’ interactions which might be useful in the ongoing search for a versatile CTX-M-inhibitor.