The widespread emergence of methicillin-resistant Staphylococcus aureus (MRSA) has dramatically eroded the efficacy of current β-lactam antibiotics and created an urgent need for new treatment options. We report an S. aureus phenotypic screening strategy involving chemical suppression of the growth inhibitory consequences of depleting late-stage wall teichoic acid biosynthesis. This enabled us to identify early-stage pathway-specific inhibitors of wall teichoic acid biosynthesis predicted to be chemically synergistic with β-lactams. We demonstrated by genetic and biochemical means that each of the new chemical series discovered, herein named tarocin A and tarocin B, inhibited the first step in wall teichoic acid biosynthesis (TarO). Tarocins do not have intrinsic bioactivity but rather demonstrated potent bactericidal synergy in combination with broad-spectrum β-lactam antibiotics against diverse clinical isolates of methicillin-resistant staphylococci as well as robust efficacy in a murine infection model of MRSA. Tarocins and other inhibitors of wall teichoic acid biosynthesis may provide a rational strategy to develop Gram-positive bactericidal β-lactam combination agents active against methicillin-resistant staphylococci.

From a tryptophan metabolic study, 3-(hydroxyacetyl)indole, indole-3-carboxaldehyde, and o-aminobenzoic acid were obtained as tryptophan metabolites from a staurosporine (1) producer, Streptomyces staurosporeus. A new tryptamine metabolite, (3aR,8aS)-1-acetyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3- b]indol-3a-ol (2), was isolated along with Nb-acetyltryptamine using S. staurosporeus fed with tryptamine. The unusual compound 2 was proposed as a further metabolite of Nb-acetyltryptamine through an enzymatic oxidative cyclization. Examination of the metabolites from the feeding of 5- and 6-fluorotryptamines using the same microorganism afforded the two novel compounds 3 and 4 as the 5- and 6-fluoro derivatives of 2. However, 5-hydroxytryptamine failed to generate the 5-hydroxy derivative of 2. Indole-ring-substituted metabolites of staurosporine (1) were not observed.

A new hydrogenated azaphilone Sch725680 (1) was isolated and identified from the culture of an Aspergillus sp. The structure elucidation of 1 was achieved based on extensive NMR spectroscopic analyses. Compound 1 showed inhibitory activity against Saccharomyces cerevisiae (PM503) and Candida albicans (C43) with MICs of 8 and 64 mg/ml, respectively.

No abstract

Two novel chemokine receptor CCR-5 inhibitors, Sch 210971 (1) and Sch 210972 (2), were isolated from the fungal fermentation broth of Chaetomium globosum by normal- and reversed-phase HPLC purifications. The structure determination of 1 and 2 was accomplished on the basis of UV, MS, and NMR spectral data analyses including COSY, NOESY, HMQC, and HMBC experiments. The structure and relative configuration of 2 were determined unequivocally by X-ray crystallographic analysis. The major component 2 demonstrated a potent inhibitory activity of IC(50) = 79 nM in the CCR-5 receptor in vitro binding assay.