Abstract The in vitro activity and spectrum of tedizolid and comparators were analyzed against 6884 Gram-positive clinical isolates collected from multiple US and European sites as part of the ...Surveillance of Tedizolid Activity and Resistance Program in 2011 and 2012. Organisms included 4499 Staphylococcus aureus , 537 coagulase-negative staphylococci (CoNS), 873 enterococci, and 975 β-hemolytic streptococci. The MIC values that inhibited 90% of the isolates within each group (MIC90 ) were 0.25 μg/mL for Staphylococcus epidermidis and β-hemolytic streptococci and 0.5 μg/mL for S. aureus , other CoNS, and enterococci. Of 16 isolates with elevated tedizolid or linezolid MIC values (intermediate or resistant isolates), 10 had mutations in the genes encoding 23S rRNA (primarily G2576T), 5 had mutations in the genes encoding ribosomal proteins L3 or L4, and 5 carried the cfr multidrug resistance gene. Overall, tedizolid showed excellent activity against Gram-positive bacteria and was at least 4-fold more potent than linezolid against wild-type and linezolid-resistant isolates. Given the low overall frequency of isolates that would be resistant to tedizolid at the proposed break point of 0.5 μg/mL (0.19%) and potent activity against contemporary US and European isolates, tedizolid has the potential to serve as a valuable therapeutic option in the treatment of infections caused by Gram-positive pathogens.
Background. While echinocandins demonstrate excellent efficacy against Candida species in disseminated infections and demonstrate potent minimal inhibitory concentration (MIC) values under standard ...susceptibility testing conditions, investigation under conditions relevant to the vaginal environment was needed. We assessed the antifungal activity and time-kill kinetics of the novel echinocandin rezafungin (formerly CD101) under such conditions, against Candida species relevant to vulvovaginal candidiasis (VVC). Methods. Susceptibility testing of fluconazole-susceptible and fluconazole-resistant C. albicans, C. glabrata, C. tropicalis, C. parapsilosis, and C. krusei was performed in RPMI at pH 7.0 and in vagina-simulative medium (VSM) at pH 4.2 for topical rezafungin, terconazole, fluconazole, and amphotericin B. Time-kill kinetics were evaluated for rezafungin and terconazole at 2, 8, 32, and 128 μg/ml over 72 hours. Results. Rezafungin MIC values were the same or 2-fold higher in VSM/pH 4.2 versus RPMI/pH 7.0. Some C. albicans terconazole MIC values were lower, but most were significantly higher in VSM than in RPMI. Rezafungin was fungicidal against 11/14 strains and near-fungicidal against the others. Terconazole (128 μg/ml) was fungicidal against C. krusei and near-fungicidal against susceptible C. parapsilosis but fungistatic versus all other strains evaluated. Conclusion. Rezafungin retained anti-Candida activity and fungicidal activity under in vitro conditions relevant to VVC.
Bacterial infection remains a serious threat to human lives because of emerging resistance to existing antibiotics. Although the scientific community has avidly pursued the discovery of new ...antibiotics that interact with new targets, these efforts have met with limited success since the early 1960s. Here we report the discovery of platensimycin, a previously unknown class of antibiotics produced by Streptomyces platensis. Platensimycin demonstrates strong, broad-spectrum Gram-positive antibacterial activity by selectively inhibiting cellular lipid biosynthesis. We show that this anti-bacterial effect is exerted through the selective targeting of β-ketoacyl-(acyl-carrier-protein (ACP)) synthase I/II (FabF/B) in the synthetic pathway of fatty acids. Direct binding assays show that platensimycin interacts specifically with the acyl-enzyme intermediate of the target protein, and X-ray crystallographic studies reveal that a specific conformational change that occurs on acylation must take place before the inhibitor can bind. Treatment with platensimycin eradicates Staphylococcus aureus infection in mice. Because of its unique mode of action, platensimycin shows no cross-resistance to other key antibiotic-resistant strains tested, including methicillin-resistant S. aureus, vancomycin-intermediate S. aureus and vancomycin-resistant enterococci. Platensimycin is the most potent inhibitor reported for the FabF/B condensing enzymes, and is the only inhibitor of these targets that shows broad-spectrum activity, in vivo efficacy and no observed toxicity.
Rezafungin is a long-acting, intravenously administered echinocandin for the treatment of candidemia and invasive candidiasis (IC). Non-inferiority of rezafungin vs caspofungin for the treatment of ...adults with candidemia and/or IC was demonstrated in the Phase 3 ReSTORE study based on the primary endpoints of day 14 global cure and 30-day all-cause mortality. Here, an analysis of ReSTORE data evaluating efficacy outcomes by baseline
species is described. Susceptibility testing was performed for
species using the Clinical and Laboratory Standards Institute reference broth microdilution method. There were 93 patients in the modified intent-to-treat population who received rezafungin; 94 received caspofungin. Baseline
species distribution was similar in the two treatment groups;
(occurring in 41.9% and 42.6% of patients in the rezafungin and caspofungin groups, respectively),
(25.8% and 26.6%), and
(21.5% and 18.1%) were the most common pathogens. Rates of global cure and mycological eradication at day 14 and day 30 all-cause mortality by
species were comparable in the rezafungin and caspofungin treatment groups and did not appear to be impacted by minimal inhibitory concentration (MIC) values for either rezafungin or caspofungin. Two patients had baseline isolates with non-susceptible MIC values (both in the rezafungin group: one non-susceptible to rezafungin and one to caspofungin, classified as intermediate); both were candidemia-only patients in whom rezafungin treatment was successful based on the day 30 all-cause mortality endpoint. This analysis of ReSTORE demonstrated the efficacy of rezafungin for candidemia and IC in patients infected with a variety of
species.
Decades of previous efforts to develop renal-sparing polyene antifungals were misguided by the classic membrane permeabilization model
. Recently, the clinically vital but also highly renal-toxic ...small-molecule natural product amphotericin B was instead found to kill fungi primarily by forming extramembraneous sponge-like aggregates that extract ergosterol from lipid bilayers
. Here we show that rapid and selective extraction of fungal ergosterol can yield potent and renal-sparing polyene antifungals. Cholesterol extraction was found to drive the toxicity of amphotericin B to human renal cells. Our examination of high-resolution structures of amphotericin B sponges in sterol-free and sterol-bound states guided us to a promising structural derivative that does not bind cholesterol and is thus renal sparing. This derivative was also less potent because it extracts ergosterol more slowly. Selective acceleration of ergosterol extraction with a second structural modification yielded a new polyene, AM-2-19, that is renal sparing in mice and primary human renal cells, potent against hundreds of pathogenic fungal strains, resistance evasive following serial passage in vitro and highly efficacious in animal models of invasive fungal infections. Thus, rational tuning of the dynamics of interactions between small molecules may lead to better treatments for fungal infections that still kill millions of people annually
and potentially other resistance-evasive antimicrobials, including those that have recently been shown to operate through supramolecular structures that target specific lipids
.
In screening for antifimgal inhibitors from fungi, four related antifungal agents have been isolated from the cultivation of Aspergillus fumigatus ATCC 20857. These agents were initially produced by ...the microorganism growing on a solid millet-based medium. A liquid medium containing both glucose and glycerol has also been developed in which these antibiotics are produced in two phases. These novel compounds, sphingofungins A, B, C, and D, show a limited spectrum of antifungal activity but were especially effective against Cryptococcus species.
A new β-1, 3-D-glucan synthesis inhibitor, L-687, 781 is produced by the cultivation of Dictyochaeta simplex ATCC 20960. L-687, 781 exhibits potent in vitro antifungal activity as well as ...anti-Pneumocystis activity in a rat model.
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