Hybrid antibiotics – clinical progress and novel designs

ABSTRACT

Introduction: There is a growing need for new antibacterial agents, but success in development of antibiotics in recent years has been limited. This has led researchers to investigate novel approaches to finding compounds that are effective against multi-drug resistant bacteria, and that delay onset of resistance. One such strategy has been to link antibiotics to produce hybrids designed to overcome resistance mechanisms.

Areas covered: The concept of dual-acting hybrid antibiotics was introduced and reviewed in this journal in 2010. In the present review the authors sought to discover how clinical candidates described had progressed, and to examine how the field has developed. In three sections the authors cover the clinical progress of hybrid antibiotics, novel agents produced from hybridisation of two or more small-molecule antibiotics, and novel agents produced from hybridisation of antibiotics with small-molecules that have complementary activity.

Expert opinion: Many key questions regarding dual-acting hybrid antibiotics remain to be answered, and the proposed benefits of this approach are yet to be demonstrated. While Cadazolid in particular continues to progress in the clinic, suggesting that there is promise in hybridisation through covalent linkage, it may be that properties other than antibacterial activity are key when choosing a partner molecule.

KEYWORDS:

• Antibiotic resistance
• Cadazolid
• clinical progress
• dual-action drugs
• hybrid antibiotics
• multi-targeting

Article highlights

• The rise and spread of MDR and XDR bacteria means that there is a continued need to develop new treatments, both to combat resistant strains and also to address potential for development of resistance.

• Dual-acting hybrid antibiotics have been proposed as a promising strategy to address this urgent need. In 2010 Baasov and Pokrovskaya reviewed early efforts in this area, and some key questions arose from that work: 1) How would hybrid antibiotics fare in the clinic? 2) Have new hybrid antibiotics been shown to delay onset of resistance?

• Several hybrid antibiotics have been evaluated with some success in clinical trials in humans. Cadazolid and TD-1792 are actively undergoing Phase III trials for CDAD and cSSSI.

• Since 2010 there have been many attempts to produce novel hybrid antibiotics, mostly designed to be dual-acting. However, despite several showing good activity against bacteria resistant to the parent antibiotics, we found only one example where dual-activity against the targets of both parents was demonstrated.

• Alternative hybridisation strategies involving combining an antibiotic with a potentiator, or through ‘Trojan-horse’ strategies such as linking an antibiotic to a siderophore have also been investigated.

• Although true dual-action has been hard to achieve, hybridisation of antibiotics has led to agents that have demonstrated impressive activity and that have made some progress in the clinic. The changes in physicochemical properties brought by hybridisation should be a key consideration when designing hybrid antibiotics.

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Acknowledgments

The authors thank Stephen East, Mark Whittaker and Peter Warn for reading the manuscript and for helpful comments.

Declaration of interest

The authors are employees of and are supported by Evotec (UK) Ltd. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.