�-lactam antibiotics constitute the most diverse and extensively used group of antimicrobials in the world. This antibiotic class inhibits bacterial cell wall biosynthesis by mimicking the D-alanyl-D-alanine subunit of peptides that are a precursor to the cell wall structure. The acylation reaction forms a long lasting acyl-enzyme intermediate between the �-lactam and a catalytic serine residue. Upon forming this intermediate, the biosynthesis process is severely inhibited and can ultimately lead to bacterial cell death. Though the identity of the main catalytic residue is known (i.e. serine), acylation mechanistic details including the general base responsible for deprotonating the serine and the general acid that protonates the nitrogen of the �-lactam ring remain unknown. Some details of this have been gleaned from studies of the deacylation step, however characterization of the acylation mechanism has proven more difficult (largely due to rapid turnover) and many questions remain unanswered. Recently, my research group has elucidated details that will greatly contribute to unraveling many of the outstanding questions; for example 1. protonation state assignment of key active site residues (i.e. Lys65 and His298) and determination of their likely roles preceding antibiotic deactivation in DD-peptidases; 2. chemical level details of the acylation enzyme reaction mechanism in DD-peptidases; 3. identification of antibiotic - enzyme intermolecular interactions that govern binding and specificity in DD-peptidases and �-lactamases.

Can peptidomimetic antibiotics overcome bacterial resistance? Elucidating molecular level binding and specificity details of DD-peptidases and �-lactamases

247th National Meeting (2014)

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