First-In-Class Inhibitor of Ribosomal RNA Synthesis with Antimicrobial Activity against <i>Staphylococcus aureus</i>

We report the discovery of the first bacterial ribosomal RNA (rRNA) synthesis inhibitor that has specific antimicrobial activity against methicillin-resistant <i>Staphylococcus aureus</i> (MRSA). A pharmacophore model was constructed on the basis of the protein–protein interaction between essential bacterial rRNA transcription factors NusB and NusE and employed for an <i>in silico</i> screen to identify potential leads. One compound, (<i>E</i>)-2-{[(3-ethynylphenyl)­imino]­methyl}-4-nitrophenol (MC4), demonstrated antimicrobial activity against a panel of <i>S. aureus</i> strains, including MRSA, without significant toxicity to mammalian cells. MC4 resulted in a decrease in the rRNA level in bacteria, and the target specificity of MC4 was confirmed at the molecular level. Results obtained from this work validated the bacterial rRNA transcription machinery as a novel antimicrobial target. This approach may be extended to other factors in rRNA transcription, and MC4 could be applied as a chemical probe to dissect the relationship among MRSA infection, MRSA growth rate, and rRNA synthesis, in addition to its therapeutic potential

Study flow chart.

<p>Study flow chart.</p

Cervical intraepithelial neoplasia grade 2 across continents.

<p>Cervical intraepithelial neoplasia grade 2 across continents.</p

Cervical adenocarcinoma and adenosquamous cell carcinoma across continents.

<p>Cervical adenocarcinoma and adenosquamous cell carcinoma across continents.</p

Prevalence and attribution of HPV52 and HPV58 among cervical lesions in Eastern Asia.

<p>Prevalence and attribution of HPV52 and HPV58 among cervical lesions in Eastern Asia.</p

Prevalence and attribution of HPV52 and HPV58 across different lesion grades in Eastern Asia and other parts of the world.

1<p>Relative prevalence, no. of HPV52-positive cases regardless of single- or multiple-type infection/total no. of HPV-positive cases.</p>2<p>% of cases with HPV52 single-type infection +% of cases with HPV52 multiple-type infection × attribution factor. Attribution factor  =  no. of cases with HPV52 single-type infection/no. of cases with single-type infection of any HPV type.</p>3<p>Relative prevalence, no. of HPV58-positive cases regardless of single- or multiple-type infection/total no. of HPV-positive cases.</p>4<p>% of cases with HPV58 single-type infection +% of cases with HPV58 multiple-type infection × attribution factor. Attribution factor  =  no. of cases with HPV58 single-type infection/no. of cases with single-type infection of any HPV type.</p><p>CIN, cervical intraepithelial neoplasia; SCC/UNSPEC, squamous cell carcinomas and invasive cervical cancers of unspecified histology; adenocarcinoma includes cervical adenocarcinoma and adenosquamous cell carcinoma.</p><p>Prevalence and attribution of HPV52 and HPV58 across different lesion grades in Eastern Asia and other parts of the world.</p

Levels of anti-hepatitis B surface antibody (anti-HBs) after booster vaccination for young adults.

<p>Each data point represents one student aged 17–23 years, born after the adoption of universal neonatal immunization for hepatitis B. All these 69 students were negative for HBsAg and anti-HBs before booster vaccination. Anti-HBs levels were determined one month after the first dose and 2–4 months after the third dose of booster vaccination with 20 mcg of ENERGIX-B (GlaxoSmithKline Biologicals, Belgium).</p

Univariate analysis on association between HPV types and survival of patients with cervical cancer after primary treatment.

<p>¹ Alpha-9 species includes HPV-16, -31, -33, -35, -52, -58, and -67</p><p>² Alpha-7 species includes HPV-18, -39, -45, -59, -68, -70, and -85</p><p>HR, hazard ratio; CI, confidence interval; statistically significant associations are bolded</p><p>Univariate analysis on association between HPV types and survival of patients with cervical cancer after primary treatment.</p

Kaplan-Meier overall survival curve of patients aged 60 years and below compared to greater than 60 years.

<p>Kaplan-Meier overall survival curve of patients aged 60 years and below compared to greater than 60 years.</p

Age distribution of children with human parechovirus (HPeV) infection.

<p>All: all 88 children infected with HPeV. Acute GE: 27 children with HPeV regarded as a “probable” cause of acute gastroenteritis. Acute Resp: 11 children with HPeV infection regarded as a “probable” cause of acute respiratory illness. Acute Rash: 12 children with HPeV infection regarded as a “probable” cause of rash illness. Suspected Neuro: 6 children developed convulsion or pallid attack with HPeV as a coinfection with other pathogen(s).</p