J. Andrew Spencer

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BACKGROUND Until now, polymyxin resistance has involved chromosomal mutations but has never been reported via horizontal gene transfer. During a routine surveillance project on antimicrobial resistance in commensal Escherichia coli from food animals in China, a major increase of colistin resistance was observed. When an E coli strain, SHP45, possessing(More)
The structure of the L1 metallo-beta-lactamase from the opportunistic pathogen Stenotrophomonas maltophilia has been determined at 1.7 A resolution by the multiwavelength anomalous dispersion (MAD) approach exploiting both the intrinsic binuclear zinc centre and incorporated selenomethionine residues. L1 is unique amongst all known beta-lactamases in that(More)
Metallo-beta-lactamases are broad-spectrum zinc enzymes, able to inactivate most clinically useful beta-lactam antibiotics. Their structural and functional diversity has thus far limited the understanding of their catalytic mechanism, therefore thwarting the rational design of a common inhibitor. On the basis of the recent availability of structures of(More)
Metallo-beta-lactamases (mbetals) confer broad-spectrum resistance to beta-lactam antibiotics upon host bacteria and escape the action of existing beta-lactamase inhibitors. SPM-1 is a recently discovered mbetal that is distinguished from related enzymes by possession of a substantial central insertion and by sequence variation at positions that maintain(More)
Alignment of DNA sequences found upstream of aphA6 and all bla(NDM-1) genes displays 100% identity. This identity continues 19 bp into the bla(NDM-1) gene such that the first 6 amino acids of aphA6 and bla(NDM-1) are the same. Furthermore, the percent GC content (GC%) of aphA6 is considerably lower than that of bla(NDM-1) and the GC% within the bla(NDM-1)(More)
Relaxation rates for folding and unfolding of two proteins have been measured over a range of denaturant concentrations to examine the reaction pathways leading to the late transition state. The proteins were chosen for their marked differences in both kinetic and structural properties. Results for the N-terminal domain of phosophoglycerate kinase (N-PGK),(More)
(+/-)-UB-165 (1) is a potent neuronal nicotinic acetylcholine receptor (nAChR) ligand, which displays functional selectivity between nAChR subtypes. Using UB-165 as a lead structure, two classes of racemic ligands were synthesized and assessed in binding assays for three major nAChR subtypes (alpha4beta2, alpha3beta4, and alpha7). The first class of(More)
The metallo-beta-lactamase L1 from Stenotrophomonas maltophilia was cloned, overexpressed, and characterized by spectrometric and biochemical techniques. Results of metal analyses were consistent with the cloned enzyme having 2 mol of tightly bound Zn(II) per monomer. Gel filtration chromatography demonstrated that the cloned enzyme exists as a tightly held(More)
The synthesis and beta-lactamase inhibitory activity of four 6-(mercaptomethyl)penicillinates and the four corresponding 6-(hydroxymethyl)penicillinates are described. These penicillins include both C6 stereoisomers as well as the sulfide and sulfone oxidation states of the penam thiazolidine sulfur. All compounds were evaluated as inhibitors of(More)
Carbapenems are the most potent β-lactam antibiotics and key drugs for treating infections by Gram-negative bacteria. In such organisms, β-lactam resistance arises principally from β-lactamase production. Although carbapenems escape the activity of most β-lactamases, due in the class A enzymes to slow deacylation of the covalent acylenzyme intermediate,(More)