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Principal Investigator: ROBERT A. BONOMO
Organization: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
Gram-negative pathogens producing metallo-β-lactamases, MBLs, are a significant threat to our public health
as treatment options against bacteria possessing these resistance determinants are extremely limited. In
general, MBLs are the most worrisome carbapenemases, inactivating “last resort” β-lactams (e.g., imipenem
and meropenem) and resist all commercially available β-lactamase inhibitors (BLIs). The main challenge in
MBL inhibitor design is exploiting the reaction mechanism as it relates to the structural diversity of the 3 distinct
subclasses (B1, B2, and B3). Based on this approach, our consortium has successfully designed a series of
innovative compounds, bisthiazolidines (BTZs) and thiazolidines (TZs), inspired on a non-β-lactam
“penicillin core” decorated with specific metal binding groups. To date, BTZs and TZs are unique potent, non-
toxic, “cross-class” MBL inhibitors. Recently, we determined the structural basis of their inhibitory action, and
their microbiological activity (bactericidal when combined with a carbapenem). This inspires confidence in the
ability of BTZs and TZs to be effective against MBL producing Gram-negative bacteria. Interestingly, novel TZs
exhibit similar properties and potencies and in certain cases are superior to BTZs.
The overarching objectives of this project are to embark upon a “high risk-high reward” program in drug
discovery to develop an effective oral MBL inhibitor that is absorbed sufficiently from the gastrointestinal (GI)
tract and can be partnered with an oral carbapenem, tebipenem pivoxil (Tbp-Pvx). We are co-opting an
established strategy, the addition of a pivoxil group, which has been successful in at least two commercial
formulations (cefditoren pivoxil and tebipenem pivoxil) and adapting it to our developmental compounds (BTZs
and TZs). Since parenteral inhibitors for serine carbapenemases are already in clinical use (e.g., avibactam,
relebactam and vaborbactam) and only a few truly MBL inhibitors are in development (QPX7728 and
taniborbactam), our unique and specific formulation will address an unmet medical need, i.e. that of an oral
cross-subclass MBL inhibitor. By the nature of its components, Tbp-Pvx is also intended to be stable
against extended-spectrum β-lactamases (ESBLs) and class C cephalosporinases (AmpCs), which are
resistance determinants often present in MBL-producing strains. Additionally, we will mitigate the problems
associated with cephalosporins (resistance selection). As a lead compound, we have identified a potent BTZ (L
syn CS319) that effectively lowers MICs to within the susceptible range when paired with a carbapenem. As an
alternative, we have also synthesized potent TZ derivatives. We propose to develop the first oral
carbapenem and MBL inhibitor formulation to be considered for development that overcomes difficult to
treat carbapenem resistant infections mediated by MBLs. Our experimental evaluations stem from close
partnership with scientists in Argentina and Uruguay and will involve a closer collaboration with the Wound
Infections Department (WID) and the Experimental Therapeutics (ET) Branch of the Walter Reed Army
Institute of Research (WRAIR) via the Geneva Foundation. After establishing “proof of concept” in the murine
thigh infection model, the ultimate clinical applications will be in skin and soft tissue, and bone and joint
infections. These are clear priorities for the Veterans Health Administration and the US Military.
Terms: <Achievement><Achievement Attainment><Alimentary Canal><Animal Model><Animal Models and Related Studies><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Argentina><Armed Forces Personnel><Bacteria><Binding><Binding Proteins><Bioavailability><Biological><Biological Availability><Blood Serum><Bone Infection><Carbapenems><Carboxylic Acids><Ccra beta-lactamase><Cephalosporin Amido-beta-Lactam Hydrolase><Cephalosporin beta-Lactamase><Cephalosporinase><Cephalosporins><Chemicals><Clinical><Collaborations><Coupled><Development><Digestive Tract><Drug Precursors><Evaluation><Exhibits><Experimental Therapies><Extended-spectrum beta-lactamase><Extended-spectrum β-lactamase><Formulation><Foundations><G24 protein><GI Tract><Gastrointestinal Tract><Gastrointestinal tract structure><Goals><Gram-Negative Bacteria><Hydrolysis><Imipemide><Imipenem><Industry><Infection><Intestinal Absorption><Investigation><Investigational New Drug Application><Investigational Therapies><Investigational Treatments><Knowledge><L Forms><L-Serine><Lactams><Lead><Ligand Binding Protein><Ligand Binding Protein Gene><Lytotoxicity><Mediating><Medical><Mercaptans><Mercapto Compounds><Meropenem><Metabolic><Metals><Methods><Mice><Mice Mammals><Military><Military Personnel><Miscellaneous Antibiotic><Modeling><Molecular Interaction><Murine><Mus><N-Formimidoylthienamycin><Nature><Oral><Osteomyelitis><PK/PD><Patients><Pb element><Penicillins><Physiologic Availability><Predisposition><Pro-Drugs><Prodrugs><Program Development><Property><Protein Binding><Public Health><Reaction><Research Institute><Resistance><Scientist><Series><Serine><Serum><Skin Tissue><Sulfhydryl Compounds><Susceptibility><Testing><Therapeutic><Thigh><Thigh structure><Thiols><Uruguay><Veterans Health Administration><Veterans Health Affairs><Wound Infection><absorption><acyl group><alimentary tract><alternative treatment><bactericidal><bactericide><beta lactam antibiotic><beta lactam hydrolase><beta-Lactamase><beta-Lactamase II><beta-Lactamhydrolase><beta-Lactams><biologic><bound protein><carbapenem resistance><carbapenem resistant><carbapenemase><clinical applicability><clinical application><compare to control><comparison control><cutaneous tissue><cytotoxicity><design><designing><developmental><digestive canal><drug development><drug discovery><experimental therapeutic agents><experimental therapeutics><gastrointestinal absorption><healing><heavy metal Pb><heavy metal lead><high reward><high risk><improved><in vitro testing><infected wound><inhibitor><innovate><innovation><innovative><joint infection><joint sepsis><meter><military population><model of animal><mouse model><murine model><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pathogen><pharmacokinetics and pharmacodynamics><programs><resistance to carbapenem><resistant><resistant to carbapenem><septic joint><soft tissue><stem><sulfhydryl group><thioester><tissue wound><wound><wounding><wounds><β lactam antibiotic><β-Lactamase><β-Lactams>