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Milano, Italy

Maffioli S.I.,NAICONS | Fabbretti A.,University of Camerino | Brandi L.,University of Camerino | Savelsbergh A.,Witten/Herdecke University | And 5 more authors.
ACS Chemical Biology | Year: 2013

Upon high throughput screening of 6700 microbial fermentation extracts, we discovered a compound, designated orthoformimycin, capable of inhibiting protein synthesis in vitro with high efficiency. The molecule, whose structure was elucidated by chemical, spectrometric, and spectroscopic methods, contains an unusual orthoformate moiety (hence the name) and belongs to a novel class of translation inhibitors. This antibiotic does not affect any function of the 30S ribosomal subunit but binds to the 50S subunit causing inhibition of translation elongation and yielding polypeptide products of reduced length. Analysis by fluorescence stopped flow kinetics revealed that EF-G-dependent mRNA translocation is inhibited by orthoformimycin, whereas, surprisingly, translocation of the aminoacyl-tRNA seems to be unaffected. © 2013 American Chemical Society.

Mazzetti C.,NAICONS | Mazzetti C.,CNR Institute of Biomedical Technologies | Ornaghi M.,NAICONS | Gaspari E.,NAICONS | And 4 more authors.
Journal of Natural Products | Year: 2012

Two new members of the spirotetronate class, nai414-A and nai414-B, were discovered and isolated from an Actinoallomurus sp. Their structures were established by 1D and 2D NMR, UV, and MS analyses and by chemical degradation. They showed antimicrobial and antitumor activity against Gram-positive bacteria and against human microvascular endothelial cells, respectively. Substituting bromide for chloride ions in the growth medium afforded mono- and dibrominated derivatives. © 2012 American Chemical Society and American Society of Pharmacognosy.

Maffioli S.I.,NAICONS | Iorio M.,NAICONS | Sosio M.,NAICONS | Monciardini P.,NAICONS | And 2 more authors.
Journal of Natural Products | Year: 2014

NAI-107, a lantibiotic produced by Microbispora sp. 107891, shows potent activity against multi-drug-resistant bacterial pathogens. It is produced as a complex of related molecules, which is unusual for ribosomally synthesized peptides. Here we describe the identification, characterization, and antibacterial activity of the congeners produced by Microbispora sp. 107891 and by the related Microbispora corallina NRRL 30420. These molecules differ by the presence of two, one, or zero hydroxyl groups at Pro-14, by the presence of a chlorine at Trp-4, and/or by the presence of a sulfoxide on the thioether of the first lanthionine. © 2014 The American Chemical Society and American Society of Pharmacognosy.

Jabes D.,NAICONS | Brunati C.,NAICONS | Candiani G.,Vicuron Pharmaceuticals | Riva S.,Vicuron Pharmaceuticals | And 6 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2014

NAI-603 is a ramoplanin derivative designed to overcome the tolerability issues of the parent drug as a systemic agent. NAI-603 is highly active against aerobic and anaerobic Gram-positive bacteria, with MICs ranging from 0.008 to 8 μg/ml. MICs were not significantly affected by pH (range, 6 to 8), by inoculum up to 108 CFU/ml, or by addition of 50% human serum. Against staphylococci and enterococci, NAI-603 was rapidly bactericidal, with minimum bactericidal concentration (MBC)/MIC ratios never exceeding 4. The frequency of spontaneous resistance was low at 2x to 4x MIC (≤1 × 10-6 to ≤1 × 10-8) and below the detection limit (about ≤1 × 10-9) at 8x MIC. Serial subcultures at 0.5x MIC yielded at most an 8-fold increase in MICs. In a systemic infection induced by methicillin-resistant Staphylococcus aureus (MRSA), the 50% effective dose (ED50) of intravenous (i.v.) NAI-603 was 0.4 mg/kg, lower than that of oral (p.o.) linezolid (1.4 mg/kg) and subcutaneous (s.c.) teicoplanin (1.4 mg/kg) or vancomycin (0.6 mg/kg). In neutropenic mice infected with vancomycin-resistant enterococci (VRE), the ED50s for NAI-603 were 1.1 to 1.6 mg/kg i.v., compared to 0.5 mg/kg i.v. of ramoplanin. The bactericidal activity was confirmed in vivo in the rat granuloma pouch model induced by MRSA, where NAI-603, at 40 mg/kg i.v., induced about a 2- to 3-log10-reduction in viable bacteria in the exudates, which persisted for more than 72 h. The pharmacokinetic (PK) profiles of NAI-603 and ramoplanin at 20 mg/kg show similar half-lives (3.27 and 3.80 h, respectively) with the maximum concentration (Cmax) markedly higher for NAI-603 (207 μg/ml versus 79 μg/ml). The favorable pharmacological profile of NAI-603, coupled with the absence of local tolerability issues, supports further investigation. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

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