Gail G. Hammond

Antibiotic sensitization using biphenyl tetrazoles as potent inhibitors of Bacteroides fragilis metallo-β-lactamase

BACKGROUND High level resistance to carbapenem antibiotics in gram negative bacteria such as Bacteroides fragilis is caused, in part, by expression of a wide-spectrum metallo-beta-lactamase that hydrolyzes the drug to an inactive form. Co-administration of metallo-beta-lactamase inhibitors to resistant bacteria is expected to restore the antibacterial activity of carbapenems. RESULTS Biphenyl tetrazoles (BPTs) are a structural class of potent competitive inhibitors of metallo-beta-lactamase identified through screening and predicted using molecular modeling of the enzyme structure. The X-ray crystal structure of the enzyme bound to the BPT L-159,061 shows that the tetrazole moiety of the inhibitor interacts directly with one of the two zinc atoms in the active site, replacing a metal-bound water molecule. Inhibition of metallo-beta-lactamase by BPTs in vitro correlates well with antibiotic sensitization of resistant B. fragilis. CONCLUSIONS BPT inhibitors can sensitize a resistant B. fragilis clinical isolate expressing metallo-beta-lactamase to the antibiotics imipenem or penicillin G but not to rifampicin.

Synthesis and SAR of thioester and thiol inhibitors of IMP-1 Metallo-β-Lactamase

Potent thioester and thiol inhibitors of IMP-1 metallo-β-lactamase have been synthesized employing a solid-phase Mitsunobu reaction as the key step.

Dicationic 2-fluorenonylcarbapenems: Potent anti-MRS agents with improved solubility and pharmacokinetic properties

The synthesis and biological evaluation of a series of dicationic-substituted 2-fluorenonylcarbapenems is described. This class of compounds showed enhanced water solubility while maintaining potent activity against MRS. Introduction of a 1-beta-methyl substituent was found to improve pharmacokinetics.

Structure-activity relationships of biphenyl tetrazoles as metallo-β-lactamase inhibitors

Resistance to carbapenem antibiotics in Gram-negative bacteria is due, in part, to expression of a wide spectrum metallo-β-lactamase, which renders the drug inactive. Biphenyl tetrazoles containing 3-n-butyl-1-phenylpyrazole-5-carboxylates or the corresponding 5-ethyl esters were found to inhibit metallo-β-lactamases as well as renal dehydropeptidase I to a lesser extent.

Synthesis and activity of 2-(sulfonamido)methyl-carbapenems: Discovery of a novel, anti-MRSA 1,8-naphthosultam pharmacophore

A series of 1beta-methyl carbapenems substituted at the 2-position with lipophilic, acyclic and cyclic (sulfonamido)methyl groups was prepared and evaluated for activity against resistant gram-positive bacteria. From these studies, the 1,8-naphthosultamyl group emerged as a novel, PBP2a-binding, anti-MRSA pharmacophore worthy of further exploration.

Synthesis and properties of 2-(naphthosultamyl)methyl-carbapenems with potent anti-MRSA activity: discovery of L-786,392.

A series of 1beta-methyl-2-(naphthosultamyl)methyl-carbapenems bearing dicationic groups on the naphthosultamyl moiety was prepared and evaluated for activity against resistant gram-positive bacteria. Based on a combination of excellent in vitro antibacterial activity, acceptable mouse acute toxicity, and a desirable fragmentation pattern on beta-lactam ring opening, the analog 2g (L-786,392) was selected for extended evaluation.

Benzothiazolylthio carbapenems: potent anti-MRSA agents

Abstract A series of sulfur-linked benzothiazolyl carbapenems has been prepared and evaluated against a battery of microorganisms. Many of the compounds displayed good activity against methicillin-resistant Staphylococcus aureus (MRSA). Data is presented which delimits the pharmacophore and provides a preliminary SAR.