Determination of
            <i>In Vitro</i>
            Activities of Solithromycin at Different pHs and Its Intracellular Activity against Clinical Isolates of Neisseria gonorrhoeae from a Laboratory Collection

Mallegol, Julia; Fernandes, Prabhavathi; Seah, Christine; Guyard, Cyril; Melano, Roberto G.

doi:10.1128/aac.00564-13

Cited by 19 publications

(18 citation statements)

References 31 publications

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“…Mutations in the MtrR protein, the repressor of the mtrCDE operon, also contribute to the high-level macrolide-resistant phenotype, but only for reduced susceptibility or moderate resistance to azithromycin (37). Low solithromycin MICs were observed even in isolates with AZM MICs of Ն2,048 g/ml, as recently reported (27,38). In contrast to AZM, which binds only one site on the 23S ribosomal subunit, solithromycin would have three sites of interaction, thereby enhancing its activity due to the higher number of binding sites (39).…”

Section: Discussionsupporting

confidence: 69%

Azithromycin Resistance Is Coevolving with Reduced Susceptibility to Cephalosporins in Neisseria gonorrhoeae in Ontario, Canada

Allen

Seah

Martín

et al. 2014

Antimicrob Agents Chemother

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d Azithromycin (AZM) is routinely recommended as a component of dual therapy for gonorrhea in combination with third-generation cephalosporins (3GC). In this study, we examined the prevalence of AZM-resistant (AZM r ) Neisseria gonorrhoeae from July 2010 to February 2013, assessed the rate of concurrent cephalosporin resistance under the current treatment recommendations, and analyzed the clonal distribution of AZM r isolates in Ontario, Canada. Nineteen AZM r clinical isolates (one per patient; MIC, >2 g/ml) were included in the study. Susceptibility profiles of these isolates to 11 antibiotics, molecular typing, characterization of macrolide resistance mechanisms, and penicillin-binding protein 2 (PBP2) patterns were determined for all the isolates. Two groups were defined based on AZM r level; group A isolates displayed high-level resistance (MIC, >2,048 g/ml) due to mutations (A2143G) in the four copies of the 23S rRNA rrl gene, and group B isolates had moderate resistance to AZM (MICs, 2 to 8 g/ml, C2599T mutation in the rrl gene), with a subgroup belonging to sequence type 3158 (ST3158) (n ‫؍‬ 8), which also showed reduced susceptibility to 3GC (MICs, 0.12 to 0.25 g/ml, PBP2 pattern XXXIV). This AZM r phenotype was not observed in previous provincial surveillance in 2008 (the ST3158 clone was found, with AZM MICs of 0.25 to 0.5 g/ml associated with mtrR mutations). We hypothesized that the AZM mutant prevention concentration (MPC) in the ST3158 subpopulation we found in 2008 was higher than the MPC in wild-type isolates (AZM MIC, <0.031 g/ml), increasing the chances of additional selection of AZM r mutations. Full AZM resistance is now emerging in this clone together with reduced susceptibility to 3GC, threatening the future efficacy of these antibiotics as therapeutic options for treatment of gonorrhea.

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Section: Discussionsupporting

confidence: 69%

Azithromycin Resistance Is Coevolving with Reduced Susceptibility to Cephalosporins in Neisseria gonorrhoeae in Ontario, Canada

Allen

Seah

Martín

et al. 2014

Antimicrob Agents Chemother

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“…In contrast to AZM, which binds only one site on the 23S ribosomal subunit, evidence suggests that solithromycin has three sites of interaction with the 23S ribosomal subunit (30), thereby enhancing its activity due to the higher number of binding sites. These multiple interactions may explain the better anchoring of solithromycin to the ribosome even in the presence of mutations at key positions (i.e., A2058-A2059 [E. coli numbering]) (31).…”

Section: Discussionmentioning

confidence: 99%

Antimicrobial Activity of Solithromycin against Clinical Isolates of Legionella pneumophila Serogroup 1

Mallegol

Fernandes

Melano

et al. 2014

Antimicrob Agents Chemother

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The activity of solithromycin was evaluated against clinical Legionella pneumophila serogroup 1 (Lp1) isolates (n ‫؍‬ 196) collected in Ontario, Canada, from 1980 to 2011. Its in vitro activity was compared to that of azithromycin (AZM) using the broth microdilution method. Solithromycin had a MIC 50 of <0.015 g/ml and a MIC 90 of 0.031 g/ml, making its activity at least 8-fold to 32-fold higher than that of AZM (MIC 50 and MIC 90 , 0.125 g/ml and 1 g/ml, respectively). Ninety-nine percent of the isolates had MICs for solithromycin ranging from <0.015 g/ml to 0.031 g/ml, whereas 83.6% of the isolates showed MICs for AZM ranging from 0.062 g/ml to 0.25 g/ml. Interestingly, 96.7% (30 out of 31 clinical isolates) identified with higher AZM MICs (0.5 g/ml to 2 g/ml) belonged to the clinically prevalent sequence type 1. To investigate the intracellular activity of solithromycin, in vitro invasion assays were also performed against a subset of representative Lp1 isolates internalized within human lung epithelial cells. Solithromycin and AZM both inhibited growth of all intracellular Lp1 isolates at 1؋ or 8؋ MICs, displaying bacteriostatic effects, as would be expected with protein synthesis inhibitor rather than bactericidal activity. Solithromycin demonstrated the highest in vitro and intracellular potency against all Lp1 isolates compared to AZM. Given the rapid spread of resistance mechanisms among respiratory pathogens and the reported treatment failures in legionellosis, the development of this new fluoroketolide, already in phase 3 oral clinical studies, constitutes a promising alternative option for the treatment of legionellosis.

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“…These results revealed the inverse relationship between pH and antimicrobial activity of CNPs, which corroborates the findings of other studies. [37][38][39] In a prior study conducted by Mallegol et al, 40 the effect of pH on the activity of azithromycin against N. gonorrhoeae at pH 5 was investigated. The study was carried out at an acidic pH to cover the conditions that the antibiotic could be exposed to during gonococcal infection, intracellularly, and in the extracellular milieu.…”

Section: Dovepressmentioning

confidence: 99%

<p>Antibacterial Activity of Chitosan Nanoparticles Against Pathogenic N. gonorrhoea</p>

Alqahtani

Aleanizy

Tahir

et al. 2020

IJN

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The emergence of Neisseria gonorrhoeae strains that are resistant to the most commonly used antibiotics represents a great concern for global public health. This challenges the effectiveness of clinical treatment regimens and demands the development of alternative antigonococcal agent. In this regard, chitosan nanoparticles (CNPs) are known to have antimicrobial activity against a wide range of pathogens. Thus, they have become a potential candidate for combatting this era of multi-drug resistance. This study aims to formulate CNPs, characterize their physicochemical properties, and examine their antimicrobial activity against gonococcus. Materials and Methods: The ionic gelation method was used to prepare CNPs of different concentrations. Characterization for their particle size (PZ), polydispersity index (PDI), and zeta potential (ZP) was performed. The anti-microbial activity of CNPs was investigated against 13 WHO N. gonorrhoeae reference strains, using the broth dilution method. Cytotoxicity of CNPs and their effect on bacterial adhesion to HeLa cells were investigated. Results: The average PZ and ZP of the prepared NPs were increased when the concentration of chitosan was increased from 1 to 5 mg/mL and found to be in the range of 193 nm ± 1.9 to 530 nm ± 13.3, and 14 mV ± 0.5 to 20 mV ± 1, respectively. Transmission electron microscopes (TEM) images revealed spherical NPs, and the NPs had a low PDI value of ≤0.27. The formed CNPs produced antibacterial activity against all tested strains, including those resistant to multiple antibiotics, with a minimum inhibitory concentration (MIC 90) of 0.16 to 0.31 mg/ mL and a minimum bactericidal concentration (MBC) of 0.31 to 0.61 mg/mL. Of note, at all MIC 90 and MBC, the CNPs had no significant cytotoxic effect on HeLa cells and reduced bacterial adhesion to these cells at MBC doses. Conclusion: The present work findings suggest the potential of the CNPs for the treatment of gonorrhoea.

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Determination of In Vitro Activities of Solithromycin at Different pHs and Its Intracellular Activity against Clinical Isolates of Neisseria gonorrhoeae from a Laboratory Collection

Cited by 19 publications

References 31 publications

Azithromycin Resistance Is Coevolving with Reduced Susceptibility to Cephalosporins in Neisseria gonorrhoeae in Ontario, Canada

Azithromycin Resistance Is Coevolving with Reduced Susceptibility to Cephalosporins in Neisseria gonorrhoeae in Ontario, Canada

Antimicrobial Activity of Solithromycin against Clinical Isolates of Legionella pneumophila Serogroup 1

<p>Antibacterial Activity of Chitosan Nanoparticles Against Pathogenic N. gonorrhoea</p>

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