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

Abstract

bAs 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.

Halogenated Antimicrobial Agents to Combat Drug-Resistant Pathogens

“…A novel ketolide derivative was developed by linking macrolide and quinolone units (macrolones) to combat resistance against macrolides and lincosamines. The halogenated derivatives of these macrolones were the most potent derivatives of the pharmacophore examined and potently reduced the viabilities of several multidrug resistant strains of E. coli and S. pneumoniae (Fajdetić et al, 2010) (Paljetak et al, 2016). Also, halogenated analogs of 4''-O-(ω-quinolylamino-alkylamino) propionyl derivatives of macrolides potently inhibited macrolide-resistant Streptococcus.…”

From Erythromycin to Azithromycin and New Potential Ribosome-Binding Antimicrobials

“…Compared to azithromycin or to quinolones, most of the compounds exhibited improved and superior in vitro potency against the key erythromycin-resistant respiratory pathogens [ 27 , 28 , 29 ]. They show activity on eryS- and MLSb-resistant S. pneumoniae (ribosome methylation as the major mechanisms of erythromycin resistance) in the murine pneumonia model [ 74 ]. For macrolones no demonstration has confirmed yet that their functional target is the ribosome or that they inhibit protein synthesis.…”

“…As is the case with “classical” macrolides, which are known to possess favorable pharmacokinetic properties by accumulating in inflammatory cells, the macrolone class of compounds, with its distinct structural features, shows equal or better accumulation in inflammatory cells [ 75 ]. Unlike macrolides and ketolides, macrolones showed rapid bactericidal effects against H. influenzae , and they exhibited equal or lower in vitro resistance development potential than azithromycin and telithromycin in S. pneumoniae , H. influenzae , S. aureus , and M. catarrhalis [ 74 ]. Macrolones have a low clearance, large volume of distribution, and long half-life, complying with once-daily dosing potential [ 74 ].…”

“…Unlike macrolides and ketolides, macrolones showed rapid bactericidal effects against H. influenzae , and they exhibited equal or lower in vitro resistance development potential than azithromycin and telithromycin in S. pneumoniae , H. influenzae , S. aureus , and M. catarrhalis [ 74 ]. Macrolones have a low clearance, large volume of distribution, and long half-life, complying with once-daily dosing potential [ 74 ]. However, even after considerable data about its in vitro activity, mode of action, in vivo efficacy, and recognizing macrolones as superior in comparison to the known macrolide antibiotics, true potential of that compound class should still be evaluated after obtaining more detailed structural insight into binding mode to the ribosome.…”

Current Molecular Therapeutic Agents and Drug Candidates for Mycobacterium abscessus

“…To overcome the existing macrolide resistance mechanisms, new drug discovery and drug design have been evaluated. For instance, a novel class of macrolide antibiotics named “macrolones” comprising a macrocyclic moiety, linker, and either free or esterified quinolone group showed excellent antibacterial activity towards erythromycin-resistant gram-positive and gram-negative bacterial strains ( Čipčić Paljetak et al, 2016 ). Furthermore, the macrolones possess a low clearance, large volume of distribution, long half-life and possess favourable pharmacokinetic properties by accumulating in inflammatory cells, consequently complying with a once-daily dosing potential ( Munić Kos et al, 2013 ).…”