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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - resistance evolution (Bacterial evolution of hypersensitivity and resistance against antimicrobial peptides)

Teaser

Summary

Cationic antimicrobial peptides (CAPs) are a new class of highly promising anti-bacterial alternatives to the conventional small molecule antibiotics currently used in the clinics. However, a crucial question remains to be answered: Is there an overlap in the mechanisms conferring resistance to small-molecule antibiotics and CAPs? This issue is of central importance, as a promising CAP candidate to be developed for use in the clinics should not share resistance mechanisms with antibiotics but must be effective against both antibiotic sensitive and antibiotic resistant strains.

Work performed

We applied an integrated systems biology approach to study the susceptibilities of antibiotic resistant Escherichia coli strains towards CAPs. For the first time, we systematically determined the relationship between antibiotic resistance and susceptibility to CAPs. When a bacterial population faces a single antibiotic and evolves resistance against it, they frequently become multidrug resistant. By contrast, as we show in our work, antibiotic resistance often renders bacteria more susceptible to CAPs. We also identified the underlying molecular mechanisms leading to an increased sensitivity to CAPs. We show that a canonical multidrug resistance conferring mutation in marR elevates the susceptibility to CAPs up to 40%. This finding is of extreme importance since mutations in marR are clinically relevant and usually responsible for multi-drug resistance.

Moreover, we identified an antimicrobial peptide that, when administered as an adjuvant, restores antibiotic effectiveness against antibiotic resistant strains. This CAP could not only render antibiotic resistant strains sensitive to that antibiotic, but also mitigate de novo evolution of antibiotic resistance. This observation is of high importance. It suggests that CAPs could be used as adjuvants during antibiotic therapy for two reasons: they restore the sensitivity of antibiotic resistant bacteria and also delay the emergence of antibiotic resistance. We found a promising lead peptide for future rational development of combination therapies.

Final results

In summary, the novelties of the project are as follows:
â€¢ Provides a systems-level proof that antibiotic resistance frequently leads to collateral sensitivity to CAPs.
â€¢ Identifies clinically relevant antibiotic resistance mutations that elevate susceptibility towards antimicrobial peptides.
â€¢ Identifies a CAP that, if added as an adjuvant, not only restores the effectiveness of the antibiotic, but also mitigates the de novo evolution of antibiotic resistance.

Based on the above points, we believe that this work would be of broad interest to researchers from a wide variety of fields, such as microbiology, systems biology, medicinal chemistry and drug development. The first papers on this subproject are under review.