Antibiotics with a Built-in OFF Switch

03/23/2020

Widespread use of antibiotics in healthcare and agriculture has led to their artificial accumulation in natural habitats. Emerging evidence illustrates a wide range of negative consequences of antibiotic waste accumulation in ecosystems. These include short-term and long-term adverse effects on the structure and function of microbial communities involved in biogeochemical cycling and organic matter degradation; contamination of water, plants, stockbreeding, and aquaculture products in the food chains; and the development of resistomes—reservoirs of antibiotic resistance genes among both pathogenic and nonpathogenic bacteria. Ideally, antibiotics should deactivate rapidly once released into the environment; however, none of the currently used antibiotics meet this criterion.

In a study by Zheng et al., a research group from Texas Tech University demonstrated a new antibiotic design with a built-in “OFF” switch responsive to natural stimuli. The design is based on the self-assembly of nanoparticles from environmentally benign building blocks of polymer-grafted cellulose backbones.

The group used SAXS performed with SSRL’s beam line 4-2 to probe the interaction of such nanostructures with membranes mimicking mammalian and bacterial cells, and combined it with biochemical assays that established antibiotics cytotoxicity and enzymatic degradation.

In their nanostructured forms, the particles are harmless toward mammalian cells, but potent agents against both Gram-positive and Gram-negative bacteria, including clinical multidrug-resistant strains. Upon discharge into the environment, cellulases that are abundant in natural habitats, but not in the human body, shred the particles into antimicrobially-inactive pieces.

This study demonstrates mitigation of the environmental footprints of antibiotics using rationally-designed nanoantibiotics that can be dismantled and disabled by biorthogonal chemistry occurring exclusively in natural habitats.

References

Zheng W., et al. 2020. “Environmentally Benign Nanoantibiotics with a Built-in Deactivation Switch Responsive to Natural Habitats,” Biomacromolecules 21(6), 2187–198. [DOI:10.1021/acs.biomac.0c00163]