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Biological Methods for Microbial Control01:28

Biological Methods for Microbial Control

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Microbial-inspired antidotes to repurpose toxic compounds as antibiotics.

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    Repurposing toxic cancer drugs as antibiotics is possible using a dual strategy. This approach enhances drug safety and efficacy against resistant bacteria, offering a new path for antimicrobial development.

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    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.