John P. Dirlam

Synthesis and structure-activity relationships of thiotetronic acid analogues of thiolactomycin

3-Acetyl analogues of thiolactomycin, a thiotetronic acid natural product, were synthesized and profiled against livestock pathogens. Some analogues showed improved activity over thiolactomycin against Staphylococcus aureus and comparable activity against Pasteurella multocida. Several semisynthetically modified analogues of thiolactomycin showed no improvement in activity over thiolactomycin.

Cyclic homopentapeptides. 1. Analogs of tuberactinomycins and capreomycin with activity against vancomycin-resistant enterococci and Pasteurella

Abstract A 6a-(3′,4′-dichlorophenylamino) analog of viomycin was uncovered by a high-throughput screen against the animal health pathogen Pasteurella haemolytica, and has served as a novel lead structure for our infectious disease programs. We report herein the synthesis and activity of analogs of tuberactinomycins and capreomycin that are active against Pasteurella spp., methicillin-resistant Staphylococcus aureus, and vancomycin-resistant enterococci. This paper describes the synthesis and activity of some C-6a-substituted analogs of tuberactinomycins and capreomycin, which are active against Pasteurella spp., methicillin-resistant Staphylococcus aureus, and vancomycin-resistant enterococci.

CP-82,009, a potent polyether anticoccidial related to septamycin and produced by Actinomadura sp.

A new polyether antibiotic CP-82,009 (C49H84O17) was isolated by solvent extraction from the fermentation broth of Actinomadura sp. (ATCC 53676). Following purification by column chromatography and crystallization, the structure of CP-82,009 was elucidated by spectroscopic (NMR and MS) methods. The absolute stereochemistry was determined by a single crystal X-ray analysis of the corresponding rubidium salt. CP-82,009 is among the most potent anticoccidial agents known, effectively controlling the Eimeria species that are the major causative agents of chicken coccidiosis at doses of 5 mg/kg or less in feed. It is also active in vitro against certain Gram-positive bacteria, as well as the spirochete, Serpulina (Treponema) hyodysenteriae.

Cyclic homopentapeptides 2. Synthetic modifications of viomycin

Abstract This paper describes synthetic modifications of the C-19 position of tuberactinomycin B (viomycin) and related analogs. The in vitro antibacterial activity of selected analogs against Pasteurella multocida, Escherichia coli and methicillin-resistant Staphylococcus aureus is also discussed. Although C-19 arylation and thiolation did not improve antibacterial activity, C-19 benzyl carbamates, benzyl- and phenyl ureas were found to be more potent than the parent antibiotic.

Synthesis and SAR of azalide 3,6-ketal aromatic derivatives as potent gram-positive and gram-negative antibacterial agents

3,6-Ketals of 15-membered azalide pseudoaglycones are a novel series of macrolide antibiotics. The aromatic derivatives of the azalide 3,6-ketals demonstrated potent antibacterial activities against both Gram-positive and Gram-negative bacteria.

Chapter 13. Antibacterial Agents

Publisher Summary This chapter discusses the recent important developments of research that has focused on finding new analogs of existing classes of anti-bacterial agents, novel classes lacking cross-resistance, and novel anti-bacterial screening targets. The chapter discusses the important developments of the past year related to β-lactams, macrolides, quinolones, oxazolidinones, and tetracyclines, in addition to several less-developed or new areas that offer exciting potential, including novel screening targets. Recently, β-lactam permeation and transport mechanisms have been reviewed. In the cephalosporin area, pharmacokinetic studies of newer compounds and new information on agents, including S-1090, E1100, and “dual-action” cephalosporin-quinolone conjugates RU-59863 and 2-oxaisocephems, have appeared. New broad spectrum cephalosporins have also been described in the chapter. Several new examples of cephalosporins, containing a catechol moiety to enhance uptake into the gram-negative bacteria, have appeared. Two of these reports contain results of extensive evaluation in vitro . New carbapenems have also been reported with potent anti-pseudomonal activity. Having now witnessed the commercial introduction of several second generation macrolides, pharmaceutical scientists are poised to develop the next wave of improved macrolides. The anti-microbial and pharmacokinetic properties of most of the quinolones under development, that include a number of very promising candidates, have been discussed in the chapter. New information pertaining to the mechanisms of quinolone activity has appeared and the toxicity of this class has been reviewed. Several reviews of tetracycline antibiotics have appeared, including an account of the newest generation of tetracyclines, the glycylcyclines. Additional biological data have been reported on the two most widely profiled glycylcyclines, DMG-MINO, and DMG-DMDOT.

CP-82,996, a novel diglycoside polyether antibiotic related to monensin and produced by Actinomadura sp

SummaryA new polyether antibiotic CP-82,996 (C50H86O16) was isolated by solvent extraction from the fermentation broth ofActinomadura sp. (ATCC 63764). Following purification by silica gel column chromatography and crystallization, the structure of CP-82,996 was determined by a single crystal X-ray analysis. The structure is closely related to monensin, but is unique in that it contains two sugar groups, whereas monensin has none. The1H and13C NMR chemical shifts and assignments for CP-82, 996 were elucidated, and they were compared with those determined previously for monensin. CP-82,996 is active against certain Gram-positive bacteria, and is a very potent anticoccidial agent. It effectively controlled chicken coccidiosis caused by severalEimeria species at 5–10 ppm in feed, and is 10–20 times more potent than monensin.

Chapter 11. Antibacterial Agents

Publisher Summary Research continues to search within known antibiotic classes for improved agents, look for novel classes lacking cross-resistance, and study resistance mechanisms to approach the problem of resistant bacteria and the possible consequences. This chapter discusses the important developments of the recent times related to β-lactams, quinolones, tetracyclines, and macrolides, in addition to several less-developed areas that offer potential improvements in therapeutic options. New information, pertaining to the mechanisms of quinolone activity and toxicity, has also appeared. Topoisomerase IV may be a target for the quinolones in intact bacteria, and the accumulation of quinolones is significantly increased in post-antibiotic effect (PAE) phase cells relative to the actively growing cells. The potency of quinolones against mammalian topoisomerase II is, to a large extent, dependent on the structure of the C-7 substituent. A number β-lactams, with unusual structures, has been recognized. E1101, the isopropoxycarbonyloxymethyl ester prodrug of E1100 exhibits in effect oral absorption in laboratory animals and humans and has been the subject of an extensive chemistry and structure–activity relationship (SAR) study. The increased need for new agents for combating antibiotic-resistant bacteria has rejuvenated interest in the tetracycline class. Two common mechanisms of resistance to tetracyclines exist. The first is the removal of drug from the bacterial cell by membrane-bound efflux proteins and the second is the ribosomal protection that prevents tetracyclines from interrupting polypeptide chain elongation. The well-precedented ability of macrolides to penetrate and accumulate in various host cells has led to: (1) studies of the utility of macrolides versus infections, caused by intracellular pathogens (for example, chlamydia and enteric bacteria) and (2) further studies on uptake and effect on macrophages, neutrophils, and T-lymphocytes.