Worldwide, bacterial pathogens pose an alarming public health threat due to their resistance to current antimicrobial drugs. While antibiotics have been widely used to prevent bacterial infections over the last 50-60 years, all major bacterial pathogens now are showing resistance to currently prescribed antibiotics worldwide. Increasing drug resistance is extremely concerning because bacterial diseases are globally widespread and can move easily between countries, culminating in the current global public health crisis. Antimicrobial drug-resistant infections become life-threatening in hospitals and seriously complicate medical practices, including cancer treatments and biomedical devices. Furthermore, existing strategies for developing new antimicrobial drugs are not effective because they mainly focus on previously-exploited modes of action or derivatives of existing drug compounds that pathogens have already gained resistance to. Thus, the need for new antimicrobial products to control invasive bacterial pathogens is greater now than it has ever been. We present a novel target for the development of antimicrobial compounds which involves a critically-important metabolic process that is unique to bacteria & effectively diminishes the phenotypic resistance of bacterial pathogens.
Background:
Virulence and resistance of bacterial pathogens during infection involve phenotypic adaptation in which pathogens modulate their metabolic activity in response to changing environment and nutrient availability in the host. This phenotypic adaptation is a survival strategy and allows pathogens to persist under severely-limited nutritional environments and utilize molecules acquired from the host during infection. Mucoid (resembling mucus) phenotype is the most well-known adaptive phenotype. Several species of bacterial pathogens exhibit mucoid phenotype by secreting exopolysaccharides and form multicellular conglomerates known as biofilms. Biofilms represent a typical structured adaptation environment in which secreted exopolysaccharides facilitate adherence to surfaces, and provide a mechanism for colonization and resistance during infection. Bacteria in biofilms remain protected from administered antibiotics and become refractory to the immune system defenses.
Mucoid bacteria are among the most clinically-challenging pathogens. Mucoid phenotype is observed in highly virulent subpopulations of pathogens and is responsible for the onset and progression of disease as well as antimicrobial resistance. It also plays a critical role in the establishment of chronic infections. One particularly important example, Pseudomonas aeruginosa, generally inhabits humans but is notorious for impairing pulmonary function and damaging the lung and digestive tissues in cystic-fibrosis (CF) patients. In CF, bacterial exopolysaccharides clog the lungs and digestive system of the patients, preventing clearance and resulting in chronic infection and inflammation. Because P. aeruginosa produces biofilm in the lungs and digestive systems of CF patients, whom are unable to clear this biofilm, P. aeruginosa infection is a major cause of death among such individuals. Serious, life-threatening Pseudomonas infections can also occur in hospitalized patients, especially those on breathing machines, those with devices such as catheters, burn victims, and patients with surgical wounds.
Many additional bacteria switch to a mucoid phenotype as a response to their growth environment. In fact, under unfavorable growth conditions, many bacteria switch to an exopolysaccharide-producing mucoid phenotype and form biofilm to resist the environmental stress and adapt to unfavorable conditions. Exopolysaccharides produced by bacteria also have industrial importance as they can spoil/impair processes in paper, food, and health industries.
Summary:
We present the discovery of a “Novel Aconitase,” also referred to as aconitase C, or AcnC, as a new and unique target for developing antimicrobial products. AcnC is required for bacteria to detoxify propionic acid, a compound that is commonly generated as an intermediary metabolite in the form of propionyl CoA or propionate. If not cleared by metabolism, propionic acid/propionate/propionyl CoA becomes a toxic metabolite and inhibits the growth of bacteria, including those exhibiting the mucoid phenotype. During infection, invading pathogens need to metabolize propionic acid/propionate/propionyl CoA arising from utilization of carbon sources like cholesterol, odd chain fatty acid, and certain amino acids as well as fermentation of various sugars under limited glucose availability in host. Effective inhibition of the production or the activity of AcnC abolishes propionic acid metabolism in bacteria, resulting in significant reduction in bacterial growth and virulence expression, including biofilm production. Most bacteria have AcnC homologs (reported under the gene name acnD, and AcnD protein designation). However, there is no mammalian homolog for AcnC (or AcnD). Thus, this innovation prioritizes AcnC protein and acnC gene as unique microbial molecular targets for identifying novel and robust compounds for antimicrobial drug development. Accordingly, chemicals that inhibit either the production or activity of the AcnC protein will be useful in making bacterial pathogens more susceptible to propionic acid toxicity and to agents which generate propionic acid. Disruption of the activity or production of AcnC along with the administration of propionic acid, compounds which generate propionic acid, or of probiotic organisms that increase propionic acid levels have a deleterious and inhibitory effect on pathogenic bacteria. Inhibition of AcnC also potentiates the action of existing antibiotic drugs to inhibit the growth of bacterial pathogens.
Technical Description:
Bacterial resistance to antibiotics is usually associated with acquisition of resistance genes or due to mutations in elements relevant for the activity of the antibiotic. However, during infections, bacterial resistance to drugs typically involves non-genetic phenotypic attributes related to metabolic adaptation. Propionic acid catabolism is a critically-important metabolic process required for pathogenic bacteria to adapt, survive, and grow in the host environment. Effective inhibition of production or activity of AcnC is a novel anti-infective strategy that diminishes the phenotypic resistance of bacterial pathogens and enhances the killing action of existing antibiotic drugs.
The prioritized target, novel aconitase, is a metabolic enzyme with classifiable substrate and catalytic function. This ascertains that information about target biochemistry is available to design iterative screening strategies and to make predictions on potential antimicrobial compound chemistry at the front end of the drug discovery process. As enzyme inhibition is a major strategy for most of the drug design, identification of assayable inhibitors that act on specific site on AcnC, or related metabolic activity, is a highly promising approach for discovery of new antimicrobial drugs.
Value Proposition:
The presented antimicrobial target, novel aconitase (also referred to as AcnC protein and acnC gene) - involved in propionic acid catabolism, metabolic adaptation, and bacterial virulence - provides a new opportunity for the potential design and development of new anti-microbial, anti-infective, and anti-bacterial compounds as well as biofilm control agents.
Applications:
Inhibitors of “Novel Aconitase” (a.k.a. acnC) production or activity will serve as agents for:
Key Benefits:
Publication:
Candas M. Novel aconitase. United States Patent Application Publication U.S. 2004/0248276 A1. Pub. Date: December 9, 2004.
IP Status: US patent 7,183,100 issued.
Licensing Opportunity: This technology is available for exclusive or non-exclusive licensing.
ID Number: 09-026
Contact: otc@utdallas.edu
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