This project called Consortium for drug-resistant Gram-negative pathogen detection is an academic-industrial partnership established to address the challenges posed by the RFA Partnerships for Diagnostics to Address Antimicrobial Resistance of Select Bacterial Pathogens. The project will focus on two groups of Gram-negative bacterial (GNB) pathogens-carbapenem-resistant Enterobacteriaceae (CRE) and drug-resistant Pseudomonas aeruginosa (PA), which have been designated by the Centers for Disease Control and Prevention (CDC) as urgent threat and serious threat pathogens, respectively. These organisms are major causes of healthcare-associated infections (HAIs), but CREs are also emerging as life-threatening causes of community-onset infections (COIs). They are enormously complicated to treat, especially when they express enzymes (-lactamases) that inactivate commonly-used antimicrobial agents. This project will develop and validate an integrated diagnostic system designed to directly detect and differentiate GNBs into CREs and PA from blood and urine samples. The same system will be designed to detect all of the clinically important - lactamases, so that clinicians can make a more informed and rapid decision about which antibiotics to initiate. The integrated system is thus designed to mimic in one device most of the steps involved in a clinical microbiology laboratory to detect CREs and PA. The proposed diagnostic system is made possible because of two important innovations. One is an integrated molecular diagnostics system (iMDx) designed to rapidly separate GNBs from clinical sample and capture target GNBs for species identification. The other is called self-accelerated dimerization (SAD) assay that facilitates bacterial enzyme amplification so that the target enzyme activity can be detected in less than 10 minutes. The SAD assay will be integrated into iMDx. Together, these innovations will be refined and validated against a large panel of clinical isolates of GNBs obtained from blood stream (BSI) and urinary tract infections (UTI) in different regions of the world. The accuracy of the system will also be prospectively assessed at San Francisco General Hospital among patients hospitalized for BSI or sepsis, and catheter-associated UTI. A successful development of this system will not only improve patient clinical management, but help reduce unnecessary use of expensive, later-generation antibiotics and prevent the selection of new drug-resistant GNB pathogens in healthcare and community settings.

Public Health Relevance

This project is a partnership of an academic institution and a diagnostic company established to develop a simple and rapid test to identify drug-resistant bacteria that cause serious blood stream infections and urinary tract infections. In particular, we target a group of bacteria designated recently by the Centers for Disease Control and Prevention (CDC) as 'urgent' and 'serious' threats. The successful development of this new device will not only improve patient outcomes, but also help reduce clinical practices that contribute to the selection of drug-resistant bacteria in healthcare and community settings.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZAI1-MFH-M (J1))
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Ritchie, Alec
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University of California Berkeley
Internal Medicine/Medicine
Schools of Public Health
United States
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Maity, Santanu; Sadlowski, Corinne M; George Lin, Jung-Ming et al. (2017) Thiophene bridged aldehydes (TBAs) image ALDH activity in cells via modulation of intramolecular charge transfer. Chem Sci 8:7143-7151