Background. A high initial or peak severe acute respiratory syndrome (SARS)—associated coronavirus (SARS-CoV) load in nasopharyngeal specimens was shown to be associated with a high mortality rate. ...Because all infected individuals were devoid of preeexisting protective immunity against SARS-CoV, the biological basis for the variable virus burdens in different patients remains elusive. Methods. The nationwide SARS database in Taiwan was analyzed, and genotyping of 281 single-nucleotide polymorphisms (SNPs) of 65 genes was performed for 94 patients with SARS, to identify SNPs for which distribution between patients with or without detectable nasopharyngeal shedding of SARS-CoV was biased. Results. Titers of SARS-CoV shed in nasopharyngeal specimens varied widely, ranging from nondetectable to 108 SARS-CoV RNA copies/mL, and they were correlated positively with a high mortality rate (P < .0001, by trend test) and with early death (i.e., death occurring within 2 weeks of the onset of illness) (P = .0015, by trend test). Virus shedding was found to be higher among male patients (P = .0014, by multivariate logistic regression) and among older patients (P = .015, by multivariate logistic regression). Detectable nasopharyngeal shedding of SARS-CoV was associated with polymorphic alleles of interleukins 18 (P = .014) and 1A (P = .031) and a member of NFκB complex (reticuloendotheliosis viral oncogene homolog B RelB) (P = .034), all of which are proinflammatory in nature, as well as the procoagulation molecule fibrinogen-like protein 2 (P = .008). Conclusion. The SARS-CoV load is a determinant of clinical outcomes of SARS, and it is associated with polymorphisms of genes involved in innate immunity, which might be regulated in an age- and sex-dependent manner. The findings of the present study provided leads to genes involved in the host response to SARS-CoV infection; if substantiated with functional studies, these findings may be applicable to other newly emerged respiratory viruses (e.g., the influenza pandemic strain).
By use of pro-dual-drug concept the synthesis of 6-β-(
R)-2-(clavaminio-9-
N-yl)-2-(4-hydroxyphenylacetamido)penicillanic acid (
10), 6-β-(
R)-2-(amino)-2-(4-(clavulano-9-
...O-yl)phenylacetamido)penicillanic acid (
13), (
Z)-4-2-(amoxycillin-4-
O-yl)ethylidene-2-(clavulano-9-
O-yl)-3-methoxy-Δ
α,β-butenolide (
19), and 3-(amoxicillin-4-
O-yl)methyl-7-(phenoxyacetamido)-(1-oxo)-3-cephem-4-carboxylic acid (
23) was accomplished. Unlike penicillin G, ampicillin, or amoxicillin, these four heretofore undescribed compounds
10,
13,
19, and
23 showed notable activity against β-lactamase (βL) producing microorganisms,
Staphylococcus aureus A9606,
S. aureus A15091,
S. aureus A20309,
S. aureus 95,
Escherichia coli A9675,
E. coli A21223,
E. coli 27C7,
Pseudomonas aeruginosa 18S-H, and
Klebsiella pneumoniae A20634 TEM. In comparison with amoxicillin (
9), α-amino-substituted compound
10 and butenolide derivative
19 showed a broadened spectrum of antibacterial activity; yet they were found to be less active than
13 and
23. Like clavulanic acid (
7) or cephalosporin-1-oxide (
21), the newly synthesized compounds
10,
13,
15,
16,
19, or
23 functioned as potent inhibitors of various bacterial βLs.
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