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Principal Investigator: Alex Sajovic Moreland
Organization: XIRETSA INC.
Fiscal Year: 2024
Award: $299,995
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Antimicrobial resistance (AMR) is an existential threat to global human health, causing ~1.3M deaths and ~50M
years of life lost annually. Antibiotics are the cornerstone of modern medicine, and we stand to lose advances in
treating myriad diseases if we lose the arms race with AMR. There is an urgent need for novel antibiotics with
unique chemical structures and differentiated mechanisms of action (MOA). The ability of bacteria to rapidly
mutate and develop resistance necessitates the selection of targets that are not only essential but also the
products of multiple genes. The membrane represents such a target and has been successfully exploited by
host immune systems, antimicrobial peptides (AMPs), AMP-like therapeutics such as polymyxins, and
antiseptics. Membrane-targeting small molecules have certain favorable properties relative to AMPs, such as
simpler manufacturing and the potential for better pharmacokinetics. However, despite the promise, membrane-
targeting small molecules have yet to obtain regulatory approval due to challenges with selectivity for bacteria
and safety in vivo. We have discovered a novel class of membrane-modifying antimicrobials, called Anti-infective
Conjugated Electrolytes (ACEs), that we aim to develop into life-saving treatments for the greatest AMR threats
such as lower respiratory infections caused by K. pneumoniae. ACEs are highly selective for bacteria, rapidly
bactericidal, active in vivo, and have anti-biofilm activity, low cytotoxicity, and no hemolytic properties. Subtleties
of the MOA are still under investigation, but ACEs are not lytic and do not exert their antimicrobial activity through
non-specific membrane permeabilization or depolarization. Instead, ACEs induce membrane remodeling, which
is suspected to cause mislocalization or dysfunction of essential membrane proteins. ACE structure-activity
relationships (SAR) have been elucidated and laid the foundation for our recent partnership with NIH Center for
Combating Antibiotic Resistant Bacteria (CC4CARB). New ACE scaffolds co-designed with CC4CARB serve as
the initial subject matter for this project. We will assess ~40 ACEs synthesized by CC4CARB to elucidate
additional SAR and utilize this information to design an additional ~40 ACE derivatives of promising subfamilies
(Aim 1). From this composite set of ACEs, we will identify promising leads via a gated-tier approach (Aim 2). The
activity of derivatives will first be assessed against a panel of critical gram-negative and gram-positive pathogens.
ACEs with high activity and low cytotoxicity will pass to the second tier of in vitro activity and safety testing. The
highest performing 6-8 ACEs will then be assayed for their bactericidal kinetics and antibiofilm activity against
K. pneumoniae. Additionally, the activity of these derivates will be determined in host-relevant media as well as
a Galleria infection model. 4 ACEs will be selected for assessment of resistance development, efficacy in murine
models of lung infection caused by K. pneumoniae, in vivo safety, and pharmacokinetics (Aim 3). Successful
completion of this Phase 1 project will validate the ACE platform, identify new lead ACE subfamilies, and provide
SAR insights that can be exploited in subsequent lead optimization as part of a Phase 2 project.
Terms: <Acceleration><Airway infections><Anti-Infective Agents><Anti-Infective Drugs><Anti-Infectives><Anti-infective Preparation><Antibiotic Agents><Antibiotic Drugs><Antibiotic Resistance><Antibiotics><Antimicrobial Resistance><Antiseptics><Assay><Bacteria><Bacteria resistance><Bacteria resistant><Bacterial resistant><Benchmarking><Best Practice Analysis><Bioassay><Biological><Biological Assay><California><Cell Membrane Permeability><Cessation of life><Chemical Structure><Chemicals><Chemistry><Chest><Collaborations><Combating Antibiotic Resistant Bacteria><Competence><Death><Derivation><Derivation procedure><Development><Disease><Disorder><Drug Kinetics><Drugs><Dysfunction><E coli><E. coli><Electrolytes><Elements><Enteral><Enteric><Escherichia coli><Foundations><Functional disorder><Future><Generalized Growth><Genes><Goals><Gram-Negative Bacteria><Growth><Health><Hemolysis><Horizontal Gene Transfer><Human><Immune system><In Vitro><Infection><Investigation><K pneumoniae><K. pneumoniae><Kinetics><Klebsiella pneumoniae><Knowledge><Lateral Gene Transfer><Lead><Life><Local Anti-Infective Agents><Lower Respiratory Tract Infection><Lower respiratory infection><Lung><Lung Respiratory System><Lung infections><Lytotoxicity><Medication><Medicinal Chemistry><Membrane><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Mice><Mice Mammals><Microbial Biofilms><Miscellaneous Antibiotic><Modeling><Modern Man><Modern Medicine><Multi-Drug Resistance><Multidrug Resistance><Multiple Anti-bacterial Drug Resistance><Multiple Anti-bacterial Drug Resistant><Multiple Bacterial Drug Resistance><Multiple Drug Resistance><Multiple Drug Resistant><Murine><Mus><Mutate><NIH><National Institutes of Health><Pb element><Penetration><Performance><Persons><Pharmaceutic Chemistry><Pharmaceutical Chemistry><Pharmaceutical Preparations><Pharmacokinetics><Phase><Physiopathology><Polymyxins><Property><Research><Resistance><Resistance development><Resistance to Multi-drug><Resistance to Multidrug><Resistance to Multiple Anti-bacterial Drug><Resistance to Multiple Drug><Resistance to antibiotics><Resistant development><Resistant to Multiple Anti-bacterial Drug><Resistant to Multiple Drug><Resistant to antibiotics><Resistant to multi-drug><Resistant to multidrug><Respiratory Infections><Respiratory Tract Infections><Safety><Structure><Structure-Activity Relationship><Surface Proteins><Syndrome><Testing><Therapeutic><Thorace><Thoracic><Thorax><Time><Tissue Growth><Topical Anti-Infective Agents><Toxic effect><Toxicities><United States National Institutes of Health><Universities><Validation><anti-microbial><anti-microbial peptide><anti-microbial resistant><antibiotic drug resistance><antibiotic resistant><antimicrobial><arms race><bacterial resistance><bactericidal><bactericide><benchmark><biofilm><biologic><chemical structure function><combat><communicable disease control agent><cytotoxicity><design><designing><develop drug resistance><developing resistance><developmental><drug resistance development><drug/agent><erythrolysis><flexibility><flexible><global health><heavy metal Pb><heavy metal lead><improved><in vitro activity><in vivo><innovate><innovation><innovative><insight><intercalation><lead optimization><life year loss><manufacture><membrane permeability><membrane structure><microbial><mortality><mouse model><multi-drug resistant><multi-drug resistant bacteria><multidrug resistant><multidrug resistant bacteria><murine model><novel><ontogeny><pathogen><pathophysiology><programs><pulmonary><pulmonary infections><resistance to Bacteria><resistance to Bacterial><resistance to anti-microbial><resistant><resistant to Bacteria><resistant to Bacterial><resistant to antimicrobial><respiratory><safety testing><scaffold><scaffolding><small molecule><structure function relationship><synergism><validations><years of life lost>