Biology subjects

Adcock, R. S.

Publications and source records attributed to Adcock, R. S..

3 recordsLinked to original sources

bioRxiv2022

Validated Preclinical Murine Model for Therapeutic Testing against Multidrug Resistant Pseudomonas aeruginosa

The rise in infections caused by antibiotic resistant bacteria is outpacing the development of new antibiotics. The ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are a group of clinically important bacteria that have developed resistance to multiple antibiotics and are commonly referred to as multidrug resistant (MDR). The medical and research communities have recognized that without new antimicrobials, infections by MDR bacteria will soon become a leading cause of morbidity and mortality. Therefore, there is an ever growing need to expedite the development of novel antimicrobials to combat these infections. Toward this end, we set out to refine an existing murine model of pulmonary Pseudomonas aeruginosa infection to generate a robust preclinical tool that can be used to rapidly and accurately predict novel antimicrobial efficacy. This refinement was achieved by characterizing the virulence of a panel of genetically diverse MDR P. aeruginosa strains in this model, both by LD50 analysis and natural history studies. Further, we defined two antibiotic regimens (aztreonam and amikacin) that can be used a comparators during the future evaluation of novel antimicrobials, and validated that the model can effectively differentiate between successful and unsuccessful treatment as predicted by in vitro inhibitory data. This validated model represents an important tool in our arsenal to develop new therapies to combat MDR P. aeruginosa, with the ability to provide rapid preclinical evaluation of novel antimicrobials that can also serve to support data from clinical studies during the investigational drug development process.

microbiology↗

bioRxiv2021

Identification of Potent Small Molecule Inhibitors of SARS-CoV-2 Entry

The severe acute respiratory syndrome coronavirus 2 responsible for COVID-19 remains a persistent threat to mankind, especially for the immunocompromised and elderly for which the vaccine may have limited effectiveness. Entry of SARS-CoV-2 requires a high affinity interaction of the viral spike protein with the cellular receptor angiotensin-converting enzyme 2. Novel mutations on the spike protein correlate with the high transmissibility of new variants of SARS-CoV-2, highlighting the need for small molecule inhibitors of virus entry into target cells. We report the identification of such inhibitors through a robust high-throughput screen testing 15,000 small molecules from unique libraries. Several leads were validated in a suite of mechanistic assays, including whole cell SARS-CoV-2 infectivity assays. The main lead compound, Calpeptin, was further characterized using SARS-CoV-1 and the novel SARS-CoV-2 variant entry assays, SARS-CoV-2 protease assays and molecular docking. This study reveals Calpeptin as a potent and specific inhibitor of SARS-CoV-2 and some variants.

microbiology↗

bioRxiv2018

A Novel Compound, ML336, Inhibits VEEV Replication by Interfering with Viral RNA Synthesis.

Venezuelan equine encephalitis virus (VEEV) is an alphavirus that is endemic to Central and South America. VEEV is known to cause periodic outbreaks of encephalitis in both humans and equids. There are currently no treatments or preventatives for VEEV disease. Our group has previously reported on the development of a novel VEEV inhibitor, ML336, which showed a potent antiviral effect in cell culture models. However, the mechanism of action had yet to be elucidated. Based on the discovery of mutations conferring resistance within nonstructural proteins, we hypothesized that ML336 inhibits viral RNA synthesis. We found that ML336 was able to inhibit VEEV RNA synthesis with an IC50 value of 1.1 nM in a metabolic labelling assay. ML336 marginally affected cellular transcription at levels 20,000-fold above the IC50, and did not show any cytotoxicity up to 50 {micro}M. Using a combination of fluorography, strand-specific qRT-PCR, and a metabolic labelling assay, we found that ML336 inhibits the synthesis of all forms of VEEV RNA. Structural analogues of ML336 showed a correlation between their RNA synthesis inhibitory activity and their antiviral activity in cells, leading us to propose that the primary mechanism of action of this class of compounds is viral RNA synthesis inhibition. The activities of ML336 were highly specific to VEEV, without measurable activity against Chikungunya virus. ML336 was efficacious even in a cell-free viral RNA synthesis assay, suggesting a direct interaction with viral proteins.\n\nImportanceVenezuelan equine encephalitis virus (VEEV) is a pathogenic alphavirus that circulates in the Americas which can cause a lethal encephalitis in humans and equids. There are currently no licensed treatments or vaccines for VEEV. Due to the high potential for aerosol infection and severe outcomes, it is classified as an NIAID Category B agent. To address the unmet need for VEEV antivirals, we continue to advance a novel amidine compound, ML336, through medicinal chemistry and mechanism of action (MOA) studies. Here, we present the molecular MOA by which ML336 inhibits VEEV replication using cellular and biochemical approaches. Our data suggest that ML336 is a direct-acting antiviral that inhibits viral RNA synthesis by interfering with the viral replicase complex. Our studies provide new insights into approaches for the development of novel RNA virus replication inhibitors and the molecular mechanism of alphavirus RNA synthesis.

microbiology↗