Tetracyclines were discovered in the 1940s and exhibited activity against a wide range of microorganisms including gram-positive and gram-negative bacteria, chlamydiae, mycoplasmas, rickettsiae, and protozoan parasites. They are inexpensive antibiotics, which have been used extensively in the prophlylaxis and therapy of human and animal infections and also at subtherapeutic levels in animal feed as growth promoters. The first tetracycline-resistant bacterium, Shigella dysenteriae, was isolated in 1953. Tetracycline resistance now occurs in an increasing number of pathogenic, opportunistic, and commensal bacteria. The presence of tetracycline-resistant pathogens limits the use of these agents in treatment of disease. Tetracycline resistance is often due to the acquisition of new genes, which code for energy-dependent efflux of tetracyclines or for a protein that protects bacterial ribosomes from the action of tetracyclines. Many of these genes are associated with mobile plasmids or transposons and can be distinguished from each other using molecular methods including DNA-DNA hybridization with oligonucleotide probes and DNA sequencing. A limited number of bacteria acquire resistance by mutations, which alter the permeability of the outer membrane porins and/or lipopolysaccharides in the outer membrane, change the regulation of innate efflux systems, or alter the 16S rRNA. New tetracycline derivatives are being examined, although their role in treatment is not clear. Changing the use of tetracyclines in human and animal health as well as in food production is needed if we are to continue to use this class of broad-spectrum antimicrobials through the present century.

Tetracycline Antibiotics: Mode of Action, Applications, Molecular Biology, and Epidemiology of Bacterial Resistance

In 1998 we updated earlier descriptions of the largest family of secondary transport carriers found in living organisms, the major facilitator superfamily (MFS). Seventeen families of transport proteins were shown to comprise this superfamily. We here report expansion of the MFS to include 29 established families as well as five probable families. Structural, functional, and mechanistic features of the constituent permeases are described, and each newly identified family is shown to exhibit specificity for a single class of substrates. Phylogenetic analyses define the evolutionary relationships of the members of each family to each other, and multiple alignments allow definition of family-specific signature sequences as well as all wellconserved sequence motifs. The work described serves to update previous publications and allows extrapolation of structural, functional and mechanistic information obtained with any one member of the superfamily to other members with limitations determined by the degrees of sequence divergence.

The major facilitator superfamily.

Dangerous, antibiotic resistant bacteria have been observed with increasing frequency over the past several decades. In this review the factors that have been linked to this phenomenon are addressed. Profiles of bacterial species that are deemed to be particularly concerning at the present time are illustrated. Factors including economic impact, intrinsic and acquired drug resistance, morbidity and mortality rates, and means of infection are taken into account. Synchronously with the waxing of bacterial resistance there has been waning antibiotic development. The approaches that scientists are employing in the pursuit of new antibacterial agents are briefly described. The standings of established antibiotic classes as well as potentially emerging classes are assessed with an emphasis on molecules that have been clinically approved or are in advanced stages of development. Historical perspectives, mechanisms of action and resistance, spectrum of activity, and preeminent members of each class are discussed.

Antibiotics and Bacterial Resistance in the 21st Century

A primary goal in organ transplantation is the prevention or effective treatment of infection, the most common life-threatening complication of long-term immunosuppressive therapy. The challenges involved in achieving this goal are several: a broad range of potential sources of infection ranging from latent viruses to pathogens of both community and hospital origin; immunosuppression-induced impairment of the inflammatory response, which attenuates the signs and symptoms of invasive infection; and the adverse effects of the antimicrobial drugs used for prophylaxis and therapy, which result both from the duration of therapy required and from interactions with the immunosuppressive drugs cyclosporine and tacrolimus. Our . . .

Infection in Organ-Transplant Recipients

The influence of natural products upon drug discovery.

Chemical modification of the macrolide antibiotic oleandomycin (C-1) is described. Reductive amination of 11-acetyl-4"-deoxy-4"-oxo-oleandomycin (C-6) with ammonium acetate provides amino-oleandomycin derivative C-7 in which the 4"-amine is oriented in the axial configuration. The structure-activity relationship of a series of 4"-sulfonamide analogs prepared from amino-oleandomycin derivative C-7 is discussed. Noteworthy is the significant in vitro potency enhancement of the para-chlorobenzenesulfonamide analog C-12 over that of the parent oleandomycin. The absolute configuration of the 4"-amino-oleandomycin derivative C-7 was established through X-ray analysis of the para-iodobenzenesulfonamide analog C-14.

Synthesis and biological activities of 4"-deoxy-4"-sulfonamido-oleandomycin derivatives.

A novel 16-membered-ring macrolide agent (CP-163, 505, a reductive amination derivative of repromicin) was identified as an antibacterial against Pasteurella haemolytica, P. multocida and Actinobacillus pleuropneumoniae, important etiological agents of livestock respiratory disease. In vitro MIC50/90 analysis revealed that CP-163, 505 was more potent (4×) than tilmicosin against P. multocida, and equivalent to tilmicosin against P. haemolytica and A. pleuropneumoniae. In time kill kinetic studies, CP-163, 505 showed bactericidal activity against P. haemolytica, P. multocida and A. pleuropneumoniae and bacteriostatic activity against E. coli at 8 times its MIC. In vitro, CP-163, 505 was more potent in alkaline pH (16∼32×) and less potent in the presence of excess cations (Mg+2 and Ca+2, 4×). EDTA and PMBN increased CP-163, 505 potency against E. coli (4×) but not against the other species. Similar results were obtained with erythromycin A and tilmicosin, which were used as controls. From our data, we hypothesize that Pasteurella and Actinobacillus have an outer membrane significantly different from that of the typical enteric Gram-negative bacterium E. coli.

In vitro Microbiological Characterization of Novel Macrolide CP‐163,505 for Animal Health Specific Use.

Ring contraction of the neutral oleandrose sugar in the 14-membered-ring macrolide antibiotic oleandomycin (2) has been accomplished using [(methoxycarbonyl)sulfamoyl]triethylammonium hydroxide inner salt (1). The product of this interesting rearrangement, after methanolic hydrolysis of the 2'-acetate, is the 11-acetyl-3-O-(3"-methoxy-4"-vinylfuranosyl)oleandomycin (12). The in vitro activity of furanoside 12 is only moderately less than that of 11-acetyloleandomycin (13).

Ring contraction of oleandrose on the macrolide antibiotic oleandomycin with ((methoxycarbonyl)sulfamoyl)triethylammonium hydroxide inner salt

Two cyclic homopentapeptides, CP-101,680 and CP-163,234 [6a-(3',4'-dichlorophenylamino) analogs of viomycin and capreomycin, respectively], were identified as novel antibacterial agents for the treatment of animal disease, especially for livestock respiratory disease. The in vitro microbiological characterization of both CP-101,680 and CP-163,234 was carried out using their parent compounds, viomycin and capreomycin, as controls. This characterization included antibacterial spectrum, influence of media, inoculum size, pH, EDTA, polymixin B nonapeptide (PMBN), serum, cell-free protein synthesis inhibition, and time-kill kinetics. Our results indicated that the capreomycin analog, CP-163,234, showed slightly improved in vitro potency over the viomycin analog, CP-101,680. Both analogs showed very potent cell-free protein synthesis inhibition activity and were bactericidal against Pasteurella haemolytica, P. multocida and Actinobacillus pleuropneumoniae at the level of 4 times and 8 times MICs. CP-163,234 was bactericidal at the level of 4x and 8x MIC against E. coli, but re-growth was observed after 24 hours incubation at both concentrations of CP-101,680.

In vitro Microbiological Characterization of Novel Cyclic Homopentapeptides, CP-101,680 and CP-163,234, for Animal Health Use.

The photo "Wolff" rearrangement of readily available 2-diazoceph-3-em oxides (1) directly affords carbapen-2-ems, allowing a facile entry into a ring system previously accessible only by total synthesis, lengthly semisynthesis or fermentation. The chirality of the cephalosporin is accurately translated into the corresponding carbapenem. The resulting 1-oxocarbapenems (2) were selectively transformed through reduction into 1-oxygenated carbapenems and carbapenams (3 and 4, respectively). On microbiological screening, a carbapenem (3c) was found to possess a broad spectrum of activity. An interesting antibacterial profile was discovered for a carbapenam (26).

James A. Retsema

Papers

Synthesis and biological activities of 4"-deoxy-4"-sulfonamido-oleandomycin derivatives.

In vitro Microbiological Characterization of Novel Macrolide CP‐163,505 for Animal Health Specific Use.

Ring contraction of oleandrose on the macrolide antibiotic oleandomycin with ((methoxycarbonyl)sulfamoyl)triethylammonium hydroxide inner salt

In vitro Microbiological Characterization of Novel Cyclic Homopentapeptides, CP-101,680 and CP-163,234, for Animal Health Use.

Cephalosporins to Carbapenems: 1-Oxygenated Carbapenems and Carbapenams.