Richard J. White

Deformylase as a novel antibacterial target.

Bacterial genomics has revealed a plethora of previously unknown targets of potential use in the discovery of novel antibacterial drugs. However, so far little has emerged from this approach. Peptide deformylase is an interesting target that was discovered more than 30 years ago, but was not exploited until recently. The reawakening of interest in this target resulted from an improved understanding of the enzyme, making it a more tractable and attractive target. Information on the properties of the enzyme, such as its three-dimensional structure, the activity of inhibitors, its resistance and suitability as a target are discussed.

Development of mitoxantrone

SummaryMitoxantrone (Novantrone®; dihydroxyanthracenedione) belongs to a new structural class of antineoplastic agents, the anthracenediones. It was the outcome of a program in synthetic chemistry, at the Medical Research Division of the American Cyanamid Company, which started from a molecule with structural features predicted to favor intercalation with double stranded DNA.The initial lead compound had immunomodulatory effects and was subsequently found also to possess significant activity against transplantable murine tumors. A large series of analogues was synthesized and mitoxantrone was selected for clinical trial on the basis of its potency and excellent antitumor activity in mice. It is a cytotoxic agent that will kill both proliferating and non-proliferating cells.A variety of experiments conducted with both intact cells and cell-free systems have revealed mitoxantrones ability to bind to single stranded and double stranded RNA and DNA. The drug inhibits cellular RNA and DNA synthesis to about the same extent and causes chromosomal aberrations. In vivo experiments using murine models have demonstrated good activity for mitoxantrone against a variety of transplantable tumors including both leukemias and solid types, in many cases giving putative cures. Surprisingly, it is effective when given up to 30 days before tumor implantation. Combination studies with standard anticancer agents gave evidence of therapeutic synergy in a number of cases.Preclinical studies in several animal models indicate that mitoxantrone does not have the cumulative cardiotoxic liability associated with anthracycline antibiotics such as doxorubicin.

Combinatorial modification of natural products: synthesis and in vitro analysis of derivatives of thiazole peptide antibiotic GE2270 A: A-ring modifications

Thiazole peptide GE2270 A (1) possesses potent antimicrobial activity against many gram-positive pathogens, including methicillin resistant Staphylococcus aureus (S. aureus, MRSA; MIC(90)=0.06 microg/mL) and vancomycin resistant Enterococcus spp. (VRE; MIC(90)=0.03 microg/mL); however its poor aqueous solubility has prohibited its development for the clinical treatment of infections. An integrated combinatorial and medicinal chemistry program was employed to identify derivatives of 1 that retain activity but possess greatly enhanced aqueous solubility.

Targeting metalloenzymes: a strategy that works.

Faced with a wealth of antibacterial drug discovery targets as a result of bacterial genomics, we need to carefully select which ones to work with. Choosing bacterial metalloenzymes is one possible approach that can increase the probability of success. Metalloenzymes can be identified through specific motif searches of bacterial genomes. Current state-of-the-art medicinal chemistry allows for the design of inhibitor libraries targeting metalloenzymes and the efficient optimization of leads identified. This approach has been successfully applied to the discovery of in vivo active antibacterial agents that are inhibitors of bacterial peptide deformylase and UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase. Other bacterial metalloenzymes are open to the same approach.

Biosynthesis of ravidomycin. Use of 13C-13C double quantum NMR to follow precursor incorporation

A biosynthetic scheme is proposed for the ravidomycin aglycone. Incorporation of 13C-labeled precursors was followed by conventional and 2-dimensional NMR techniques.