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, 60 (9), 5337-48

Macrolones Are a Novel Class of Macrolide Antibiotics Active Against Key Resistant Respiratory Pathogens In Vitro and In Vivo

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Macrolones Are a Novel Class of Macrolide Antibiotics Active Against Key Resistant Respiratory Pathogens In Vitro and In Vivo

Hana Čipčić Paljetak et al. Antimicrob Agents Chemother.

Abstract

As we face an alarming increase in bacterial resistance to current antibacterial chemotherapeutics, expanding the available therapeutic arsenal in the fight against resistant bacterial pathogens causing respiratory tract infections is of high importance. The antibacterial potency of macrolones, a novel class of macrolide antibiotics, against key respiratory pathogens was evaluated in vitro and in vivo MIC values against Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, and Haemophilus influenzae strains sensitive to macrolide antibiotics and with defined macrolide resistance mechanisms were determined. The propensity of macrolones to induce the expression of inducible erm genes was tested by the triple-disk method and incubation in the presence of subinhibitory concentrations of compounds. In vivo efficacy was assessed in a murine model of S. pneumoniae-induced pneumonia, and pharmacokinetic (PK) profiles in mice were determined. The in vitro antibacterial profiles of macrolones were superior to those of marketed macrolide antibiotics, including the ketolide telithromycin, and the compounds did not induce the expression of inducible erm genes. They acted as typical protein synthesis inhibitors in an Escherichia coli transcription/translation assay. Macrolones were characterized by low to moderate systemic clearance, a large volume of distribution, a long half-life, and low oral bioavailability. They were highly efficacious in a murine model of pneumonia after intraperitoneal application even against an S. pneumoniae strain with constitutive resistance to macrolide-lincosamide-streptogramin B antibiotics. Macrolones are the class of macrolide antibiotics with an outstanding antibacterial profile and reasonable PK parameters resulting in good in vivo efficacy.

Figures

FIG 1
FIG 1
General formula for the macrolone compounds. Structures vary with respect to the macrolide scaffold (erythromycin-derived 8-a-lactame, erythromycin oxime, clarithromycin, clarithromycin carbamate, azithromycin, and roxithromycin), linker length, the type and number of heteroatoms (O or N) in the linker, and the position of the linker on the quinolone unit. X, O, N or OCH2CH2; Y, O or N; Z, halogen atom (Cl or F); R1, methyl ester of quinolone carboxylic acid.
FIG 2
FIG 2
Efficacy of compound 19 (azi-OON-Cl) in a mouse model of pneumonia induced by S. pneumoniae SP030 Erys. Compound and azithromycin were administered i.p. The MIC values of compound 19 and azithromycin were ≤0.015 and 0.03 μg/ml, respectively. (A) Number of CFU per gram of lung tissue. A statistically significant reduction in the number of CFU is designated by asterisks (***, P < 0.0001). (B) Concentration of compound in lung tissue 14 h after the last dose, given as mean values ± SEMs. AZM, azithromycin; cpd 19, compound 19.
FIG 3
FIG 3
Efficacy of compounds 19 (azi-OON-Cl) and 7 (azi-ON-Cl) in a model of mouse pneumonia induced by S. pneumoniae B 1217 with MLSb. All compounds were administered i.p. The MICs of the tested compounds were as follows: ≤0.015 μg/ml for compounds 7 and 19, 0.06 μg/ml for telithromycin, and >64 μg/ml for azithromycin. (A) Number of CFU per gram of lung tissue. A statistically significant reduction in the number of CFU is designated by asterisks (**, P < 0.001). (B) Concentration of compound in lung tissue 14 h after the last dose, given as mean values ± SEMs. AZM, azithromycin; TEL, telithromycin; cpd 19, compound 19; cpd 7, compound 7.
FIG 4
FIG 4
Efficacy of compound 6 (azi-NMeN-Cl-QMe) in a mouse model of pneumonia induced by S. pneumoniae SP030 Erys. Compound 6 and azithromycin were administered per os. The MIC values of compound 6 and azithromycin were ≤0.015 and 0.03 μg/ml, respectively. (A) Number of CFU per gram of lung tissue. A statistically significant reduction in the number of CFU is designated by asterisks (**, P < 0.001). (B) Concentration of compound in lung tissue 14 h after the last dose, given as mean values ± SEMs.

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