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Mode of action studies of the novel bisquaternary bisnaphthalimide MT02 against Staphylococcus aureus

ABSTRACT: Screening of various bisquaternary bisnaphthalimides against a variety of human pathogens revealed one compound, designated MT02, with strong inhibitory effects against gram-positive bacteria. The minimal inhibitory concentrations ranged from 0.31 µg/ml against community-acquired methicillin resistant Staphylococcus aureus (MRSA) strain USA300 to 20 µg/ml against Streptococcus pneumonia. DNA-microarray studies generated a transcriptional signature characterized by a strong increase of genes involved in DNA-metabolism, DNA-replication, SOS-response and transport of positively charged compounds. Radioactive whole cell labeling experiments indicated a strong impact of MT02 on bacterial DNA-replication. Furthermore, surface plasmon resonance and gel retardation experiments demonstrated direct binding of MT02 to DNA in a concentration dependent, reversible and sequence-unspecific manner. The data presented suggest that the bisquaternary bisnaphthalimide MT02 exerts anti-gram-positive activity by binding to DNA and thereby prohibiting appropriate DNA-replication.

ORGANISM(S): Staphylococcus aureus subsp. aureus N315 Staphylococcus aureus subsp. aureus COL Staphylococcus aureus subsp. aureus MRSA252 Staphylococcus aureus subsp. aureus Mu50 Staphylococcus aureus subsp. aureus NCTC 8325 Staphylococcus aureus subsp. aureus USA300 Staphylococcus aureus subsp. aureus MW2 Staphylococcus aureus subsp. aureus MSSA476 Staphylococcus aureus

PROVIDER: GSE23077 | GEO | 2011/01/04

SECONDARY ACCESSION(S): PRJNA131687

REPOSITORIES: GEO

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Project description:Human SARS-CoV-2 and avian IBV are highly contagious and deadly coronaviruses causing devastating respiratory diseases in human and chicken, respectively. Lacking effective therapies exacerbates the disease associated with SARS-CoV-2 and IBV infections. Thus, novel therapeutic agents are in demand for controlling viral transmission and disease progression. Mesenchymal stem cells secreted factors (secretome) proven to be safe and highly efficient alternative to stem cells in mesenchymal stem cell-based therapy (MSCT). The most favorable advantage of secretome is the bypass of the side effects of MSCT that include but not limited to tumorigenesis, immune rejection, and infection. In this study, we aimed to investigate the antiviral activities of human Wharton’s jelly mesenchymal stem cells secretome against SARS-CoV-2 and IBV infection. The half-maximal inhibitory concentrations (IC50), and cytotoxic concentration (CC50) values of hWJ-MSC secretome (hWJ-MSC-S) were determined in Vero-E6 cells. Virucidal, anti-adsorption, and anti-replication mechanisms of hWJ-MSC-S against SARS-CoV-2 and IBV infection were evaluated in vitro. In Ovo anti-IBV activity of hWJ-MSC-S was estimated using Specific pathogen-free (SPF) embryonated chicken eggs (ECEs). The antiviral efficacy of hWJ-MSC-S was determined in terms of reduction in viral infection. Protein composition of hWJ-MSC-S was analyzed by mass spectrometry analysis, and gene ontology of secretome proteins was evaluated. Our data showed hWJ-MSC-S to significantly inhibits infection of human SARS-CoV-2 and avian IBV with very low cytotoxicity and embryotoxicity profile. CC50 value of hWJ-MSC-S in Vero-E6 was 39200 µg/ml. IC50, SI values of hWJ-MSC secretome against SARS-CoV-2 were 166.6 µg/ml, and 235.29, respectively. Similarly, IC50, SI values of hWJ-MSC-S against IBV were 439.9 µg/ml, and 89.11, respectively. hWJ-MSC-S reduced PFU/ml of SARS-CoV-2 and IBV by > 90%. Antiviral mechanistic studies demonstrated that hWJ-MSC-S had >95% and >90% virucidal effects on SARS-CoV-2 and IBV infections, respectively. The anti-replication effect was approximately 87.33% against SARS-CoV-2 infection, and >90% against IBV infection. In ovo model, hWJ-MSC-S significantly inhibited IBV infection. At a concentration of 1000 µg/ml, hWJ-MSC-S reduced IBV titre from 763000 ± 32638 to 38.333 ± 6.0093 EID50/ml (>99% inhibition). Similarly, hWJ-MSC-S reduced IBV titer from 763000 ± 32638 to 1896 ± 926.1 EID50/ml (>97% inhibition) at a concentration of 500 µg/ml. In addition, 250 µg/ml concentration of hWJ-MSC-S reduce IBV titer from 763000 ± 32638 to 20380 ± 2885 EID50/ml (>96% inhibition). LC/MS-MS analysis revealed that biological processes of hWJ-MSC-S proteins were mostly related to Immunomodulatory effect. Collectively, our results not only uncovered the antiviral potency of hWJ-MSC-S against SARS-CoV-2 and IBV, but also described the mechanism by which hWJ-MSC-S inhibit viral infection. These findings could be utilized in future pre-clinical and clinical studies to develop an effective therapeutic against human COVID-19 and avian IB respiratory diseases using hWJ-MSC-S.

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Mode of action studies of the novel bisquaternary bisnaphthalimide MT02 against Staphylococcus aureus

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