A high throughput screening was used to identify 10,000 compounds with bioactive molecules to inhibit the growth of carbapenem-resistant Enterobacteriaceae.

‘A total of 79 bioactive compounds has been identified to inhibit Carbapenem-resistant Enterobacteriaceae (CRE), which is one of the biggest threat to global health.’

CRE are Gram-negative bacteria that frequently express a gene that codes for a carbapenemase-an enzyme that breaks down carbapenem and other antibiotics-and that is located on "mobile genetic elements" called plasmids, which can jump from one bacterium to another. The two most common types of CRE are carbapenem-resistant Klebsiella species and carbapenem-resistant Escherichia coli. Patients who become infected with these bacteria have few antibiotic treatment options. 




"The US Centers for Disease Control and Prevention recently classified these carbapenem-resistant organisms in their highest, most urgent antimicrobial resistance threat level," said James Kirby, MD, Director of the Clinical Microbiology Laboratory at BIDMC and an Associate Professor of Pathology at Harvard Medical School. "Unfortunately, often either no effective or only toxic antimicrobial options remain for CRE treatment. Moreover, CRE are particularly frightening as they are now increasing in prevalence across the United States and the world."
While there is a critical need for new antimicrobial agents against CRE and other emerging antibiotic-resistant bacteria, the number of new antibiotics that have been developed and approved has steadily decreased in recent decades. To identify new or existing drugs that can destroy multidrug-resistant CRE, Kirby and postdoctoral fellow Kenneth Smith, PhD examined approximately 10,000 compounds with known activity-so called known bioactive molecules including most previously FDA-approved drugs, veterinary drugs and inhibitors of various cellular processes not currently used as therapeutics.
Through a process called high throughput screening, the investigators looked to see whether any of these compounds could either directly inhibit the growth of CRE or restore the effectiveness of carbapenem against these organisms.
From these screening experiments, 79 compounds were found to inhibit CRE. Of these, three had already been approved for human and veterinary use: azidothymidine (also known as AZT, therapy for HIV infection), spectinomycin (a treatment for gonorrhea infection) and apramycin (a veterinary antimicrobial). When tested against a large number of CRE strains, the three compounds were broadly active against the strains.
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Smith added that while these drugs might be used by themselves to treat CRE infection, they could also be used as starting points for further drug development. "Specifically, these antibiotics could be structurally modified to further increase their activity and prevent resistance from developing against them," he explained.
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The antimicrobial discovery efforts in the Kirby Laboratory are supported by grants from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (R21AI119114 and R21AI112694).
Source-Newswise