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Disrupting Dogma: Investigating LPS Biosynthesis Inhibition as an Alternative Mechanism of Action of Aminoglycoside Antibiotics

Award Number: R15AI176175
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: 07/01/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Disrupting Dogma: Investigating LPS Biosynthesis Inhibition as an Alternative Mechanism of Action of Aminoglycoside Antibiotics - Project Summary With numerous Gram-negative bacterial species demonstrating antimicrobial drug resistance, the identification of new inhibitors and the optimization of existing inhibitors is necessary to enable an effective treatment of illnesses. Recent research efforts in our lab and others have demonstrated that aminoglycosides have minimal impact on protein synthesis and in fact they potently bind to heptosytransferase I (HepI) in Escherichia coli. This is an important finding, because it may allow for this class of antibiotics to be dramatically redesigned to be better drugs with fewer side effects, because the HepI and ribosome binding sites have very different sizes and they have dramatic differences in charges (HepI is positively charged, while the ribosome is negatively charged). This proposal will advance efforts to redesign aminoglycoside antibiotics to enhance HepI binding and to reduce binding to other cellular targets that can lead to side effects like oto- and nephrotoxicity. Our investigation will address three hypotheses: (1) that aminoglycosides bind to other cellular targets beyond the ribosome including heptosyltransferase enzymes, (2) understanding the HepI-aminoglycoside interactions will enable structural modification and optimization of bactericidal activity, and (3) that computational methods can enhance aminoglycoside redesign. To date, efforts to redesign aminoglycosides for more potent binding to the ribosome has failed to lead to more potent drugs, and this is likely because the mechanism of action involves other enzymes like HepI. This work promises to enhance drug discovery efforts while also providing training for students in my lab and in two upper-level biochemistry courses at Wesleyan in 21st century drug discovery methods.


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: 2023 ( Subtotal = $474,697 )
2023	2023	WESLEYAN UNIVERSITY	237 HIGH ST	MIDDLETOWN	CT	06459	LOWER CT RIVER VLY	USA	Allergy and Infectious Diseases Research	000	1	6/30/2023	NEW	$474,697
														Subtotal = $474,697

Grand Total All Awards = $474,697

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Disrupting Dogma: Investigating LPS Biosynthesis Inhibition as an Alternative Mechanism of Action of Aminoglycoside Antibiotics

Award Number: R15AI176175

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: 07/01/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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