doi: 10.1039/C5MD00394F. Epub 2015 Nov 3.
Endless Resistance. Endless Antibiotics?
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- PMID:27746889
- PMCID: PMC5060946
- DOI: 10.1039/C5MD00394F
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Endless Resistance. Endless Antibiotics?
Jed F Fisher et al. Medchemcomm..
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Abstract
The practice of medicine was profoundly transformed by the introduction of the antibiotics (compounds isolated from Nature) and the antibacterials (compounds prepared by synthesis) for the control of bacterial infection. As a result of the extraordinary success of these compounds over decades of time, a timeless biological activity for these compounds has been presumed. This presumption is no longer. The inexorable acquisition of resistance mechanisms by bacteria is retransforming medical practice. Credible answers to this dilemma are far better recognized than they are being implemented. In this perspective we examine (and in key respects, reiterate) the chemical and biological strategies being used to address the challenge of bacterial resistance.
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A simulation of the cost to discover and develop an antibacterial (preclinical and clinical research) compared to the return on the cost of the investment (on-patent and off-patent sales). This Figure is taken from p. 11 of the 2015 document “Securing new drugs for future generations: The pipeline of antibiotics” of the Wellcome Trust. The factual basis for this figure is provided in the appendix to this document. (Acknowledgement: ‘Review on Antimicrobial Resistance. Securing new drugs for future generations: the pipeline of antibiotics. 2015’).
Structure–activity development within the “Golden Age” classes of the antibiotics continues, and certainly will address the future need for new antibacterials. This Scheme displays structures (identified by their generic name and/or their registry number) that exemplify (but by no means define) the research frontiers for these classes. TheAminoglycoside class (Column 1) is represented by the late-stage clinical candidate plazomicin, having broad-spectrum activity, low toxicity, and good evasion of the aminoglycoside-modifying enzymes of resistance., Structure [1626394-79-3] is an exploratory monosulfonamide-modified derivative of sisomicin with excellent Gram-negative activity and (in mice) exceptionally reduced ototoxicity. Structure [1620221-11-5], a second exploratory aminoglycoside, combines selective deletion of alcohol functional groups (to avoid resistance enzyme modification) with a fluoro-dependent reduction of the basicity of the neighboring amine with a consequent reduction in toxicity. Among the recent developments in theβ-Lactam antibiotics (Column 2) is the reevaluation of older β-lactam structures such as temocillin and aztreonam. These latter two structures were perceived at time of their entry into the clinic as undesirably narrow-spectrum. With the proliferation of β-lactamase resistance enzymes over the past two decades, the ability of these older structures to resist hydrolysis by many β-lactamases is now regarded as advantageous. The antibacterial spectrum of aztreonam is further improved upon combination with β-lactamase inhibitors. The newβ-Lactamase Inhibitor class (Column 2) includes the diazabicyclooctane avibactam., Other members of the diazabicyclooctane class under active investigation include the MK-7615 structure and the OP-0595 structure. A second new exploratory β-lactamase inhibitor, the cyclic boronic acid RPX-7009, restores carbapenem activity to bacteria expressing the KPC β-lactamase. Macrolides within the newKetolide class (Column 3) are represented by telithromycin and by the newer fluoro-substituted solithromycin. The characterization of the rRNA methylase that confers ketolide resistance to the producingStreptomyces strains will facilitate the structure-activity development of this class, given the probable eventual transition of this activity as a resistance mechanism. New structures within theTetracycline class (Column 4) include the clinically-approved tigecyline and the exploratory structure omadacycline. Although the structural difference between the two is subtle, the latter has oral activity. A second exploratory class of new tetracyclines is the hexacyclines. Resurgent interest in bacterialGyrase/Topoisomerase Inhibitors (Column 4) is driven both by the proven clinical value of the fluoroquinolones and the consequent resistance development. A comparison of the structures of moxifloxacin, a recent generation fluoroquinolone, with that of the new exploratory structure ETX-0914 (having both Gram-positive and Gram-negative activity) shows superficial similarity (both have a modified fluoroquinoline core). Notwithstanding this similarity and the shared target, the mechanistic difference between the two is distinct., ETX-0914 is a clinical candidate targetingNeisseria gonorrhoeae. It is discussed in this review as an outstanding example of the possible value that synthetic chemical libraries may have for the discovery of new antibacterials.
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