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Multi-targeting by monotherapeutic antibacterials

A Corrigendum to this article was published on 01 February 2007

Key Points

  • Successful monotherapeutic antibacterial agents are multi-targeted, in that they interact with many enzymes or with structures that are determined by several genes, and are therefore not subject to rapid high-level endogenous resistance development.

  • Most single-enzyme inhibitors are subject to rapid endogenous resistance development and are used in combinations or as topical agents.

  • It has been proposed that the low endogenous resistance development that is seen for the successful monotherapeutic agents is a consequence of multi-targeting.

  • The targets of these agents are the penicillin-binding proteins, ribosomal RNA, topoisomerases, peptidoglycan intermediate structures, and membranes.

  • Improved versions of successful agents that overcome resistance due to target changes (from exogenous resistance mechanisms) add moieties that make new intramolecular contacts.

  • Efforts to create new multi-targeted agents have used several strategies: single pharmacophore/multi-target compounds, hybrids of two pharmacophores, and combinations of single-target inhibitors to avoid resistance development.

  • Single-target inhibitors that have a low potential for resistance development might be designed by increasing the sites of intramolecular contacts.

Abstract

Antibacterial discovery research has been driven, medically, commercially and intellectually, by the need for new therapeutics that are not subject to the resistance mechanisms that have evolved to combat previous generations of antibacterial agents. This need has often been equated with the identification and exploitation of novel targets. But efforts towards discovery and development of inhibitors of novel targets have proved frustrating. It might be that the 'good old targets' are qualitatively different from the crop of all possible novel targets. What has been learned from existing targets that can be applied to the quest for new antibacterials?

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Figure 1: β-lactam antibiotics.
Figure 2: Trans-peptidation.
Figure 3: Reactions of topoisomerases.
Figure 4: Next-generation compounds overcoming resistance.
Figure 5: Hybrid and single-target agents overcoming resistance.

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The author thanks all her mentors and colleagues in the antibacterial discovery universe for long years of productive interactions.

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The author is an independent consultant who works for a number of biotech and pharmaceutical companies involved with the discovery and development of antibacterial agents.

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Silver, L. Multi-targeting by monotherapeutic antibacterials. Nat Rev Drug Discov 6, 41–55 (2007). https://doi.org/10.1038/nrd2202

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