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Principal Investigator: ROBERT A. BONOMO
Organization: CASE WESTERN RESERVE UNIVERSITY
Fiscal Year: 2024
Award: $574,870
Funding agency: National Institute of Allergy and Infectious Diseases
The Centers for Disease Control and Prevention (CDC) designated Carbapenem-Resistant Acinetobacter
baumannii (CRAb) an “urgent threat pathogen” for which novel therapies are desperately needed. The current
COVID-19 pandemic has only accelerated the emergence of CRAb in medical intensive care units and hospitals,
creating a parallel health care crisis in the US. The combination of β-lactamase production and cell penetration
challenge every drug class used to treat CRAb. By applying novel chemistry to design more potent “cross-class”
boronic acid transition state inhibitors (BATSIs) that are effective β-lactamase inactivators, and developing a
deeper understanding of the genetic diversity of β-lactamases present in CRAb, we propose to extend our efforts
to also target class B metallo-β-lactamases (MBLs; specifically IMP-1, -14, and NDM-1, as they are the most
prevalent MBLs in Ab), and develop drugs that penetrate Ab more readily. We will build upon the efficacy of two
potent BATSIs (MB076 and CR167 that were iteratively designed in our current funding cycle) to also interact
with Zn2+ ions in the active site of MBLs, as well as penetrate CRAb more effectively. Concurrently, we discovered
that OXA β-lactamase overexpression in Ab drives significant collateral changes in bacteria consistent with
increased amidase activity. As a result, peptidoglycan integrity is impacted, and new cellular vulnerabilities were
revealed. Further studies have also shown that at least five genes become conditionally essential in OXA
expressing Ab. As a result, we propose a multidisciplinary approach to overcome CRAb using the following
strategies. Firstly, we propose that structural and mechanistic similarities in class B, C, and D β-lactamases can
be exploited to permit the design of “cross-class” inhibitors by the addition of novel functional groups (e.g., Zinc
Binding groups, ZBGs). In addition, we will design novel cyclic boronates that demonstrate interactions in the
active site that inhibit MBLs as well as serine β-lactamases. Secondly, we hypothesize that the penetration of
BATSIs into Ab can be improved and overcome by modifications of the R1/R2 side chains to enhance steric and
electronic interactions that facilitate passage through porins, specifically CarO. In addition, we will synthesize
novel BATSIs that use Fe3+ mediated transport that penetrate CRAb readily and resist efflux. We will perform
molecular modeling and structural analyses of CarO to give us insight on how to overcome this major porin
conferring imipenem resistance. Studying the mechanistic/structural features inherent to CarO and the imipenem
scaffold will facilitate our first two goals. Thirdly, we discovered that OXA β-lactamase expression in CRAb
creates new cellular vulnerabilities and that certain gene products become essential for viability, but only in OXA-
overexpressing isolates. We propose that these gene products represent novel bacterial targets that can be
inhibited by small molecules to selectively kill OXA expressing bacteria. We will use high-throughput screening
to identify compounds that selectively kill OXA expressing Ab and identify the cellular target of these inhibitors.
Terms: <A baumanni><A baumannii><A. baumanni><A. baumannii><A.baumannii><Acceleration><Acinetobacter baumanni><Acinetobacter baumannii><Active Sites><Address><Animal Testing><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Awareness><Bacteria><Bacteria resistance><Bacteria resistant><Bacterial resistant><Beta-Lactam resistant><Binding><Binding Sites><Boronic Acids><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 years><Carbapenem-resistant Acinetobacter><Categories><Cell Body><Cells><Centers for Disease Control><Centers for Disease Control and Prevention><Centers for Disease Control and Prevention (U.S.)><Chemistry><Clinical><Collection><Color><Combining Site><Cyclicity><Drug resistance><Drugs><Electronics><Enzyme Gene><Enzymes><Exhibits><Fe element><Funding><G24 protein><Genes><Genetic Diversity><Genetic Variation><Goals><Health Care Systems><Healthcare><Healthcare Systems><High Throughput Assay><Hospitals><Hot Spot><Hydrolysis><Imipemide><Imipenem><Infection><Intensive Care Units><Ions><Iron><Kinetics><L-Serine><Lactamase><Lung infections><Mediating><Medical><Medication><Medicinal Chemistry><Miscellaneous Antibiotic><Modification><Molecular><Molecular Interaction><Molecular Modeling Nucleic Acid Biochemistry><Molecular Modeling Protein/Amino Acid Biochemistry><Molecular Models><Multienzyme Complexes><Murein><N-Formimidoylthienamycin><Nature><Organism><Pathway interactions><Penetration><Peptidoglycan><Periodicity><Periplasmic Space><Pharmaceutic Chemistry><Pharmaceutical Chemistry><Pharmaceutical Preparations><Production><Property><Reaction><Reactive Site><Resistance><Rhythmicity><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><Serine><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Side><United States Centers for Disease Control><United States Centers for Disease Control and Prevention><VDAC1><VDAC1 gene><Zinc><Zn element><acylamidase><acylase><amidase><b lactam resistance><b-lactam resistant><bacterial resistance><beta lactam hydrolase><beta-Lactam Resistance><beta-Lactamase><beta-Lactamhydrolase><candidate identification><cellular targeting><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><design><designing><drug resistant><drug/agent><electronic><electronic device><enzyme complex><functional group><gene product><health care><high throughput screening><improved><in vitro activity><inhibitor><insight><interdisciplinary approach><iterative design><living system><molecular modeling><multidisciplinary approach><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutics><novel therapy><overexpress><overexpression><pathogen><pathway><periplasm><pore forming protein><porin><pulmonary infections><resistance to Bacteria><resistance to Bacterial><resistance to Drug><resistance to b lactam><resistance to beta-lactam><resistance to β-Lactam><resistant><resistant to Bacteria><resistant to Bacterial><resistant to Drug><resistant to b lactam><resistant to beta-lactam><resistant to β-Lactam><scaffold><scaffolding><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><small molecule><success><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><β-Lactam Resistance><β-Lactam resistant><β-Lactamase>