Summary: The discovery of novel small-molecule antibacterial drugs has been stalled for many years. The purpose of this review is to underscore and illustrate those scientific problems unique to the discovery and optimization of novel antibacterial agents that have adversely affected the output of the effort. The major challenges fall into two areas: (i) proper target selection, particularly the necessity of pursuing molecular targets that are not prone to rapid resistance development, and (ii) improvement of chemical libraries to overcome limitations of diversity, especially that which is necessary to overcome barriers to bacterial entry and proclivity to be effluxed, especially in Gram-negative organisms. Failure to address these problems has led to a great deal of misdirected effort.

Challenges of Antibacterial Discovery

In this review an overview is given on antibiotic resistance (AR) mechanisms with special attentions to the AR genes described so far preceded by a short introduction on the discovery and mode of action of the different classes of antibiotics. As this review is only dealing with acquired resistance, attention is also paid to mobile genetic elements such as plasmids, transposons, and integrons, which are associated with AR genes, and involved in the dispersal of antimicrobial determinants between different bacteria.

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Acquired Antibiotic Resistance Genes: An Overview

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Biosynthesis and mode of action of lantibiotics.

Vancomycin resistance exhibited by Enterococcus faecalis isolates V583, V586, and V587 is described The vancomycin MICs ranged from 32 to 64 micrograms/ml Although resistant to vancomycin, the isolates were susceptible to teicoplanin (MIC, less than or equal to 05 micrograms/ml) Such a glycopeptide susceptibility profile has not been previously described for E faecalis Time kill studies showed that vancomycin resistance adversely affected the synergistic activity that vancomycin and aminoglycoside combinations usually demonstrate against enterococci However, the ability to detect vancomycin resistance varied with the susceptibility testing method used Whereas broth microdilution, broth macrodilution, and agar dilution methods detected resistance, disk-agar diffusion and the AutoMicrobic system Gram-Positive GPS-A susceptibility card (Vitek Systems Inc, Hazelwood, Mo) did not To detect vancomycin resistance reliably and establish the incidence of such E faecalis isolates, adjustments in some susceptibility testing methods may be necessary

In vitro susceptibility studies of vancomycin-resistant Enterococcus faecalis.

Over the course of the past half century, the structural elucidation of unknown natural products has undergone a tremendous revolution Before World War II, a chemist would have relied almost exclusively on the art of chemical synthesis, primarily in the form of degradation and derivatization reactions, to develop and test structural hypotheses in a process that often took years to complete when grams of material were available Today, a battery of advanced spectroscopic methods, such as multidimensional NMR spectroscopy and high-resolution mass spectrometry, not to mention X-ray crystallography, exist for the expeditious assignment of structures to highly complex molecules isolated from nature in milligram or sub-milligram quantities In fact, it could be argued that the characterization of natural products has become a routine task, one which no longer even requires a reaction flask! This Review makes the case that imaginative detective work and chemical synthesis still have important roles to play in the process of solving nature's most intriguing molecular puzzles

https://onlinelibrary.wiley.com/doi/pdf/10.1002/anie.200590046

Chasing molecules that were never there: misassigned natural products and the role of chemical synthesis in modern structure elucidation.

A soil isolate of Actinoplanes that produces the chemically unrelated new antibiotics teichomycins A1 and A2 has been proposed as a new species named Actinoplanes teichomyceticus nov. sp. (ATCC 31121). Studies of medium and fermentation conditions indicated that the highest antibiotic titers, ca 900 u/ml, are obtained in a medium containing 1% (w/v) glucose, 1% cotton seed meal, 1% malt extract, and 0.4% yeast extract. Both teichomycin A1 and teichomycin A2 are highly active against gram-positive bacteria. Teichomycin A1 shows some activity against gram-negative bacteria. Both antibiotics cured mice experimentally infected with sensitive bacteria and showed low acute toxicity. Of the two antibiotics teichomycin A2 is the more active.

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Teichomycins, new antibiotics from Actinoplanes teichomyceticus Nov. Sp. I. Description of the producer strain, fermentation studies and biological properties.

GE37468 A is a new thiazolyl peptide antibiotic obtained by fermentation of Streptomyces sp. strain ATCC 55365. It inhibits bacterial protein synthesis by acting on elongation factor Tu and is structurally and functionally related to the GE2270 class of EF-Tu inhibitors. It is active in vitro against Gram-positive bacteria and Bacteroides fragilis, and protects mice against Staphylococcus aureus infection.

Antibiotic GE2270 a: a novel inhibitor of bacterial protein synthesis. I. Isolation and characterization.

Two strains of Actinoplanes have been isolated that produce a new peptide antibiotic named gardimycin. A detailed taxonomical study of such strains indicates that they differ between themselves and from all the described species of Actinoplanes. For this reason they are considered to be new species; for which the names A. garbadinensis nov. sp. and A. liguriae nov. sp. are proposed. The type strain of A. garbadinensis is A/10889(=ATCC 31049), the type strain of A. liguriae is A/6353 (=ATCC 31048). Studies on the medium and fermentation conditions are reported.

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Lipiarmycin, a new antibiotic from Actinoplanes. I. Description of the producer strain and fermentation studies.

Two strains of Actinoplanes have been isolated that produce a new peptide antibiotic named gardimycin. A detailed taxonomical study of such strains indicates that they differ between themselves and from all the described species of Actinoplanes. For this reason they are considered to be new species; for which the names A. garbadinensis nov. sp. and A. liguriae nov. sp. are proposed. The type strain of A. garbadinensis is A/10889 (=ATCC 31049), the type strain of A. liguriae is A/6353 (=ATCC 31048). Studies on the medium and fermentation conditions are reported.

Gardimycin, a new antibiotic from actinoplanes

A new antibiotic producing actinomyces belonging to the genus Planomonospora is described. Detailed description of its morphological and some of its biochemical characters are given. The antibiotic for which the name sporangiomycin is proposed can be produced successfully under submerged conditions. Sporangiomycin was found to belong to the depsipeptide or peptolide group of antibiotics, and is related to thiostrepton. The antibiotic is highly active in vitro against gram-positive bacteria, and protects mice from streptococcal and diplococcal infections.

Grazia Beretta

Papers

Teichomycins, new antibiotics from Actinoplanes teichomyceticus Nov. Sp. I. Description of the producer strain, fermentation studies and biological properties.

Antibiotic GE2270 a: a novel inhibitor of bacterial protein synthesis. I. Isolation and characterization.

Lipiarmycin, a new antibiotic from Actinoplanes. I. Description of the producer strain and fermentation studies.

Gardimycin, a new antibiotic from actinoplanes

Antibiotic production by new form-genera of the actinomycetales. i