Microbial-inspired antidotes to repurpose toxic compounds as antibiotics

Area of Science:

• Microbiology
• Pharmacology
• Drug Development

Background:

• Antibiotic-resistant (AMR) bacterial infections pose a significant global health challenge.
• Developing novel antimicrobials is hindered by long timelines and the need for chemical novelty to overcome existing resistance mechanisms.
• Repurposing existing drugs, particularly cancer therapeutics, offers a promising strategy to accelerate the discovery of new antibiotics with novel mechanisms of action.

Purpose of the Study:

• To establish a two-component strategy for repurposing highly toxic therapeutics as antimicrobials by enhancing their safety profile.
• To utilize the cytotoxin calicheamicin as a proof-of-concept for this repurposing strategy.
• To demonstrate the generalizability of this approach for other toxic compounds.

Main Methods:

• Engineering a conditionally-active calicheamicin drug conjugate to restrict its activity to infected tissues.
• Administering a re-engineered self-resistance enzyme as an "antidote" to neutralize off-target calicheamicin.
• Evaluating the efficacy and safety of the dual strategy in vitro against Gram-negative and Gram-positive pathogens and in a mouse model of bacterial pneumonia.

Main Results:

• The calicheamicin conjugate showed antimicrobial activity against a panel of pathogens, activated by proteases in the infected microenvironment.
• Combining the conjugate with the antidote maintained antibacterial efficacy while significantly reducing off-target toxicity.
• The dual strategy successfully improved the therapeutic index of the toxic compound.

Conclusions:

• A dual strategy combining conditional drug activation and off-target neutralization provides a generalizable framework for repurposing toxic therapeutics as antimicrobials.
• This approach addresses the safety concerns associated with using potent cytotoxins for infection treatment.
• The findings pave the way for developing new antimicrobial agents from existing drug classes that were previously considered too toxic.