Omega-alicyclic tunicamycins and analogs
Inventors
Price, Neil P. • Jackson, Michael A. • Hartman, Trina M. • Bannantine, John P.
Assignees
US Department of Agriculture USDA
Publication Number
US-12245589-B2
Publication Date
2025-03-11
Expiration Date
2042-04-12
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Abstract
The invention relates to new tunicamycin structures comprising N-acyl groups metabolically integrated into the terminus of the TUN via the Streptomyces branched chain fatty acid pathways and variants thereof, and methods of preparing such new tunicamycin structures. The invention further relates to antibacterial compositions comprising such new tunicamycin structures, and methods for using such antibacterial compositions for killing Gram-positive bacteria.
Core Innovation
The invention provides new tunicamycin structures called omega-alicyclic tunicamycins (OATs), which comprise N-acyl groups metabolically integrated into the terminus of the tunicamycin N-acyl chains via the Streptomyces branched chain fatty acid pathways. These new compounds include chemically modified variants through catalytic hydrogenation and/or reduction of tunicamycin double bonds, producing TunR1- and TunR2-type OATs. The production method involves fermenting tunicamycin-producing Actinomycetes strains in liquid culture with small organic carboxylic acids to direct the incorporation of unique omega-alicyclic groups.
The problem addressed is the urgent need for new tunicamycin antibiotic adjuvants that retain antibacterial activity but with reduced mammalian toxicity. Natural tunicamycins are potent inhibitors of bacterial cell wall biosynthesis enzymes but are inherently toxic to eukaryotes due to inhibition of conserved N-glycosylation pathways. Prior tunicamycin variants have shown antibacterial activity with reduced eukaryotic toxicity; however, new derivatives with novel omega-position substituents are needed to improve therapeutic profiles and overcome antimicrobial resistance.
The invention solves this problem by integrating small alicyclic organic carboxylic acids, such as cyclopropanecarboxylic acid through cycloheptanecarboxylic acid and their unsaturated analogs, into the omega position of tunicamycin N-acyl chains. This metabolic incorporation yields novel OATs with varying chain lengths and branching patterns. Subsequent chemical hydrogenation produces TunR1 and TunR2 OAT variants with enhanced antibacterial activity especially against Gram-positive bacteria and Mycobacterium species, while reducing eukaryotic toxicity. The unique omega-alicyclic substituents enable specific binding interactions with bacterial target enzymes, contributing to their potent antibacterial and antimycobacterial effects.
Claims Coverage
The claims cover seven main inventive features related to novel N-acyl-tunicamycin variants, their compositions, methods of use against Gram-positive bacteria, methods of disinfecting surfaces, and preparation methods.
N-acyl-tunicamycin variant comprising omega-alicyclic substituents
An N-acyl-tunicamycin variant comprising small carboxylic acids integrated at the omega position of the tunicamycin N-acyl chain via Streptomyces branched chain fatty acid biosynthesis.
Antibacterial compositions containing the N-acyl-tunicamycin variant
Antibacterial compositions comprising at least one of the N-acyl-tunicamycin variants of the invention.
Combined antibiotics in antibacterial compositions
Antibacterial compositions that include at least one N-acyl-tunicamycin variant combined with an antibiotic, where the antibiotic can be a β-lactam antibiotic, a non-β-lactam antibiotic, or a combination thereof.
Method of killing Gram-positive bacteria using the antibacterial composition
A method of killing Gram-positive bacteria in or on an animal by administering an effective amount of the antibacterial composition comprising the N-acyl-tunicamycin variant.
Method of killing Gram-positive bacteria with combined antimicrobial agents
A method of killing Gram-positive bacteria in or on an animal by administering an effective amount of an antibacterial composition comprising at least one N-acyl-tunicamycin variant and a β-lactam antibiotic, non-β-lactam antibiotic, or both.
Method for disinfecting objects or surfaces using N-acyl-tunicamycin variants
A method of disinfecting an object or surface contaminated with Gram-positive bacteria by applying an effective amount of the N-acyl-tunicamycin variant to kill the bacteria.
Preparation method of N-acyl-tunicamycin variants by fermentation
A method of preparing N-acyl-tunicamycin variants by fermenting an aerobic tunicamycin-producing Actinomycetes strain in liquid culture in the presence of small organic carboxylic acids.
The claims collectively define novel omega-alicyclic N-acyl-tunicamycin variants, their compositions with or without other antibiotics, methods of treatment of Gram-positive bacterial infections and disinfection, and the preparation by substrate-directed fermentation.
Stated Advantages
Reduction in eukaryotic toxicity compared to natural tunicamycins while retaining potent antibacterial activity.
Enhanced antibacterial activity especially against Gram-positive bacteria and Mycobacterium species, including improved inhibition of biofilm formation.
Synergistic effect with β-lactam antibiotics and potential to overcome antibiotic resistance mechanisms.
Ability to produce a diverse family of tunicamycin analogs through metabolic incorporation and chemical modification.
Cost-effective production by fermentation with commercially available small alicyclic carboxylic acid precursors.
Documented Applications
Use as antibacterial agents for killing Gram-positive bacteria in or on animals.
Combination with β-lactam or non-β-lactam antibiotics to enhance antibacterial efficacy and reduce required antibiotic doses.
Disinfecting objects or surfaces contaminated with Gram-positive bacteria.
Treatment of infections caused by Mycobacterium species including pathogenic Mycobacterium avium subsp. paratuberculosis.
Inhibition of mycobacterial biofilm formation contributing to antimicrobial activity.
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