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Bactericidal antibiotics targeting lipoprotein transport in Gram-negative bacteria

Award Number: R01AI187556
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 11/20/2024
PERIOD OF PERFORMANCE END DATE: 10/31/2029

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Bactericidal antibiotics targeting lipoprotein transport in Gram-negative bacteria - Project Summary/Abstract: Our research is focused on the synthesis and biological study of antibiotics to address the growing problem of modern multi-drug resistant (MDR) pathogens of critical threat. By introducing three key structural variations within the scaffold of an established inhibitor of the localization of lipoproteins (lol) pathway, we have synthesized novel antibiotics with superior potencies against MDR Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae). Crucially, these more potent antibiotics induce a much lower frequency of spontaneous resistance in E. coli (FoR ~10-9) than the previously reported inhibitor (FoR ~10-7). We propose to diversify and improve the modular platform we have developed to synthesize large numbers of candidate antibiotics with improved potencies and optimized pharmacokinetic and pharmacodynamic profiles, which will be evaluated with in vitro and, where appropriate, in vivo studies. Furthermore, we aim to deepen the understanding of the mechanism of action of our molecules by cryo-EM imaging of the molecules bound to their target, the lolCD2E lipoprotein transport machinery. This will also inform structure-based design of future antibiotics candidates.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $749,417 )
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	1	11/20/2024	NEW	$749,417
														Subtotal = $749,417

Grand Total All Awards = $749,417

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Bactericidal antibiotics targeting lipoprotein transport in Gram-negative bacteria

Award Number: R01AI187556

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 11/20/2024

PERIOD OF PERFORMANCE END DATE: 10/31/2029

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