In vitro activities of the novel bicyclolides modithromycin (EDP-420, EP-013420, S-013420) and EDP-322 against MDR clinical Neisseria gonorrhoeae isolates and international reference strains.

OBJECTIVES: New antimicrobials are essential to prevent gonorrhoea becoming an untreatable infection. Herein, the in vitro activities of the novel bicyclolides modithromycin (EDP-420, EP-013420, S-013420) and EDP-322 against Neisseria gonorrhoeae strains were investigated and compared with antimicrobials currently or previously recommended for treatment of gonorrhoea. METHODS: MICs (mg/L) were determined using an agar dilution method (modithromycin and EDP-322) or Etest (seven antimicrobials) for a large geographically, temporally and genetically diverse collection of clinical N. gonorrhoeae isolates (n = 225) and international reference strains (n = 29), including diverse MDR and XDR isolates. RESULTS: The MIC range, modal MIC, MIC50 and MIC90 of modithromycin and EDP-322 were 0.004-256, 0.25, 0.25 and 1 mg/L and 0.008-16, 0.5, 0.5 and 1 mg/L, respectively. The activities of modithromycin and EDP-322 were mainly superior to those of azithromycin and additional antimicrobials investigated. In general, there was no cross-resistance with other antimicrobials. CONCLUSIONS: Modithromycin and EDP-322 exhibited high levels of in vitro activities against N. gonorrhoeae, including isolates resistant to azithromycin, cefixime, ceftriaxone, spectinomycin, ampicillin, tetracycline and ciprofloxacin. However, some cross-resistance with high-level azithromycin resistance (MIC = 4096 mg/L) was observed. Modithromycin and EDP-322 could be effective options for treatment of gonorrhoea, particularly for cases resistant to extended-spectrum cephalosporins and as a part of an antimicrobial combination therapy regimen. Nevertheless, it is important to detail the in vitro selection, in vivo emergence and mechanisms of resistance, pharmacokinetics/pharmacodynamics in humans and optimal dosing, and perform appropriate randomized controlled clinical trials.

Pharmacodynamic profiling of modithromycin: assessment in a pneumococcal murine pneumonia model.

The pharmacodynamic profile of modithromycin (EDP-420, EP-013420, S-013420), a novel bicyclolide, was evaluated in a neutropenic pneumococcal murine pneumonia model. Streptococcus pneumoniae median minimum inhibitory concentrations (MICs) for five genotypically diverse isolates ranged from 0.016 µg/mL to 0.125 µg/mL and were unaffected by macrolide or penicillin resistance determinants. The modithromycin dosing regimens (total daily doses of 3.125-1000 mg/kg/day) were derived from the pharmacokinetic profile of the compound in infected mice and were selected to produce a wide range of exposures. Dose-response relationships characterised using the Emax model demonstrated high correlations both with the ratio of the area under the concentration-time curve to MIC (AUC/MIC) and the ratio of the maximum drug concentration to MIC (Cmax/MIC). However, dose fractionation studies suggest that the AUC/MIC is the predominant driver of in vivo efficacy. The free drug AUC/MIC (fAUC/MIC) required for stasis and for 80% of maximum activity ranged from 4 to 53 and 25-99, respectively. The fAUC/MIC needed to achieve a 1 log reduction in bacterial density, which is a conventional measure of the required exposure in man to reliably predict efficacy, ranged from 9 to 69. These data demonstrate the in vitro and in vivo potency of modithromycin against S. pneumoniae irrespective of its phenotypic profile to the macrolides or penicillin.

Effects of EDP-420 on penicillin-resistant and quinolone- and penicillin-resistant pneumococci in the rabbit meningitis model.

OBJECTIVES: To test the efficacy of EDP-420, a new ketolide, in experimental pneumococcal meningitis and to determine its penetration into the CSF. METHODS: The experimental rabbit model was used in this study and EDP-420 was tested against a penicillin-resistant and a penicillin- and quinolone-resistant mutant. EDP-420 was also tested against both strains in time-killing assays over 8 h in vitro. RESULTS: In experimental meningitis, EDP-420 produced a bactericidal activity comparable to the standard regimen based on a combination of vancomycin with ceftriaxone against a penicillin-resistant Streptococcus pneumoniae and a penicillin- and quinolone-resistant S. pneumoniae isolate. The penetration of EDP-420 into inflamed meninges was 38% after an i.v. injection of 10 mg/kg. The bactericidal activity of EDP-420 was also confirmed in in vitro time-killing assays. CONCLUSIONS: EDP-420 is an efficacious alternative treatment in pneumococcal meningitis, especially when resistant strains are suspected.

Synthesis and antibacterial activity of a novel class of 4'-substituted 16-membered ring macrolides derived from tylosin.

Novel 4'-substituted 16-membered ring macrolides were synthesized by the cleavage of the mycarose sugar of tylosin and subsequent modification of 4'-hydroxyl group. This new class of macrolide antibiotics exhibited potent activity against some key erythromycin-resistant pathogens.

Synthesis of novel 4'-substituted 16-membered ring macrolide antibiotics derived from leucomycins.

A series of novel 4'-substituted 16-membered ring macrolides was synthesized by the cleavage of the mycarose sugar and subsequent modification of 4'-hydroxyl group. This new class of macrolides antibiotics is acid stable. The synthetic methodology described here is expected to find application in the synthesis of new generation of macrolides that target the emerging bacterial resistance.

Synthesis of new 14-membered macrolide antibiotics via a novel ring contraction metathesis.

[reaction: see text] A novel ring opening ring closing metathesis (ROM-RCM) was demonstrated for cyclic conjugated dienes, effecting the excision of a C(2)H(2) unit and a net ring contraction. Applying the ring contraction metathesis, new 14-membered ring macrolide antibiotics were synthesized in a single step from existing 16-membered ring macrolides. This new class of macrolide antibiotics will provide access to new therapeutics for the treatment of macrolide-resistant bacterial infections.