ELUCIDATING THE ANTIMICROBIAL & ANTIVIRAL ACTIVITY OF AN UNDEREXPLORED CLASS OF ORGANOBISMUTH COMPOUNDS
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2022
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Infections of antibiotic-resistant pathogens pose an ever-increasing threat to mankind. The investigation of novel approaches for tackling the issue of antimicrobial resistance (AMR) must be part of any global response to this problem if an unwanted reversion to the pre-penicillin era of medicine is to be avoided 1. One such promising avenue of research is looking into the potential of metallodrugs as a solution. Given the historical usage of bismuth compounds in the treatment of certain types of bacterial infections before the treatment of modern antibiotics and its interesting safety profile despite its heavy-metal grouping has made it a driving interest in its basic and applied research 2. Specific research efforts are focused on the development of novel Bi-based compounds, nanoparticles and composites with applications in treating cancer and microbial infections, imaging, theranostics and biosensing 3. Moreover, while metal agents have demonstrated their value as potential antimicrobial and anticancer agents, their antiviral activities have been rarely explored. Despite its growing interests in the medicinal chemistry landscape, organobismuth chemistry is far less developed in comparison to other main-group organometallic chemistry due to two obstacles. First, the C–Bi bond is weak (bond disassociation energy = 46 kcal/mol), making it prone to dismutation, a substituent scrambling process, which complicates the synthesis of unsymmetrical triarylbismuthanes of the general formula Ar21Ar2Bi (Ar1 ≠= Ar2) 4. However, the Hyvl lab at the University of Hawaii at Manoa has designed an efficient two-step synthetic protocol that affords the synthesis of a electronically diverse set of heteroleptic triarylbismuthanes without the formation of dismutated contaminants. The long-term goal of this study is to use the lead structures identified in this work to facilitate the development of novel antimicrobials and antivirals. The immediate objective of the study is to elucidate the antimicrobial and antiviral activities of this group of organobismuth compounds. Given bismuth’s historical use in treating microbial infections before the advent of modern antibiotics, such as syphilis and Helicobacter pylori, we hypothesize that these organobismuth compounds may exhibit a comparable level of antimicrobial activity. Moreover, while metal compounds have demonstrated their applications as antimicrobial and anticancer agents, their antiviral activities have rarely been explored. Due to the novelty of the structure of this underexplored class of compounds, we also hypothesize that these compounds may exert their activity through other modes of action rather than the better understood mechanisms of Bi(III). In the first aim, we screened thirty-one unique organobismuth compounds for their various levels of antimicrobial activities in the context of multiple Streptococcus spp., Staphylococcus aureus strains, and several species of Gram-negative organisms. Additionally, we determined the minimum inhibitory concentration (MIC) for each individual compound that passed initial antimicrobial activity screenings. Additionally, we also determined a range of concentrations at which each compound displays to be cytotoxic to Vero and human embryonic kidney (HEK293T) cells. We found that of the thirty-one unique compounds, twenty-eight exhibited some level of antimicrobial activity in a dose-dependent manner. While the observed activity showed variability between different species and strains of Gram-positive organisms, there did appear to be stronger levels of inhibition skewed towards strains of S. aureus, more so towards strains of methicillin-resistant S. aureus (MRSA) in certain compounds; however, we do not see any inhibitory activity against any Gram-negative bacteria. These data suggest that the targets of for some of these compounds may be specific to S. aureus and even more specifically to MRSA strains in certain contexts. Moreover, we found that twenty-one compounds demonstrate very low levels of cytotoxicity, being well tolerated even at the highest concentration tested (30 µM) displaying no noticeable toxicity when compared to healthy untreated controls measured by MTT assay.
In the second aim, we investigated the potential antiviral activity for each of the thirty-one unique compounds. Using recombinant vesicular stomatitis viruses (rVSV), we identified a total of twenty positive hits. Additionally, we found seventeen compounds that demonstrate significant levels of antiviral activity while simultaneously showing no noticeable levels of cytotoxicity even at the highest assayed concentration. Of these positive hits, we did see some overlap with lead compounds described in the previous aim assessing antimicrobial activity. However, we were also able to identify nine hit compounds that solely demonstrated antiviral activity to rVSV pseudotyped viruses. In these structures we are able to observe preliminary structure activity relationships (SARs) and how substitution at certain positions affects compound activity. Preliminary work has qualitatively shown that some compounds are capable of also inhibiting Dengue virus serotype 2 (DENV-2). These results suggest that the activity conferred by these compounds may have the potential to affect additional virus families beyond what has been investigated here. Moreover, when examining compounds under pre-treatment conditions versus virucidal conditions, we found that the compounds are more likely to act directly on the cell to mediate inhibition of viral replication and not directly on the virus itself; however, the specific mechanisms of how they do so remain unclear. If this is indeed the case, these findings may implicate their capacity to act as broad-spectrum antiviral agents.
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Pharmacology, Virology, Microbiology, antimicrobial, antiviral, bismuth, drug discovery, organobismuth, pharmacology
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73 pages
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