Antibiotic resistance has posed a threat to public health long before the outbreak of COVID-19, and is now being described as “the silent pandemic”. In the United States, according to CDC’s 2019 Antibiotic Resistance Threats, more than 2.8 million antibiotic-resistant infections occur each year, and approximately 35,000 people die as a result. The evolution of resistance is largely driven by the overuse of antibiotics. β-lactam antibiotics (e.g., penicillins, cephalosporins, carbapenems) are the most successful class of antibiotics, constituting 60% of worldwide antibiotic usage, and are among the most effective agents for treatment of infectious disease. One major acquirable mechanism for β-lactam resistance is the production of β-lactamases which break down β-lactams to metabolites incapable of binding to PBPs (Penicillin-binding proteins). A variety of colorimetric, fluorescent and chemiluminecent β-lactamase probes have been developed for detection of lactam-resistant bacteria. The nonspecific or autofluorescence background from varies types of patient specimens remain a major challenge for rapid detection of resistant microorganisms. We tackled this challenge by developing a dual-caged 3,7-diesterphenoxazine probe CDA that requires sequential activation by β-lactamase and hydrogen peroxide for rapid fluorescence detection of urinary tract infection resistant to cephalosporin antibiotics within 2 hours. To catch resistant bacteria with limited volumes        of other body fluids, we further improved the sensitivity by developing a lactam caged, dabcyl quenched luciferin substrate D-Bluco which reports as low as 10<sup>2</sup> colony-forming unit per milliliter resistant bacteria in a 30-min bioluminescence assay. These unique designs of CDA and D-Bluco afford superior sensitivity and hold promises for translation into point-of-care diagnostics.

Toward point-of-care detection of lactam-resistant bacteria

ACS Spring 2022

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