Meropenem Prodrugs for XDR-TB

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis is the leading cause of bacterial infectious disease deaths worldwide. Drug-resistant strains (MDR and XDR-TB) are an emerging problem and could lead to significant issues in the US because over half of the cases are in foreign born persons. Recently, the combination of the carbapenem, meropenem, and clavulanate was shown to be active against XDR-TB strains in vitro and importantly effective against nonreplicating bacilli. Meropenem only has a one-hour half-life and is administered only by injection. The objectives of this application are to synthesize prodrugs of meropenem that are orally bioavailable. Three prodrug strategies have been designed 1) Make a non-toxic acyloxycarbonyloxy esters (proxetil, suberolyl prodrugs) 2) Synthesize valeryl or dipeptidyl esters that are taken up by PepT1, an intestinal dipeptide transporter and 3) Prepare a bivalent prodrug that releases meropenem and clavulanate simultaneously. The prodrugs could also be used for oral switch therapy for serious Gram-negative infections caused by organisms such as Pseudomonas or Acinetobacter. Prodrugs will be evaluated both in vitro and also in vivo in guinea pigs. Metabolic stability and Caco-2 permeability studies will be done to insure adequate release and uptake. Bioavailability of five candidate prodrugs will be determined in a crossover study after administration of intravenous meropenem and oral prodrugs. Finally, for the best prodrug, meropenem penetration into lung and spleen will be evaluated after oral dosing compared to an intravenous meropenem infusion. Efficacy studies will be conducted in a BSL-3 laboratory in the guinea pig model of TB.