Dissecting the Mechanisms of Linezolid Resistance in a Drosophila melanogaster Infection Model of Staphylococcus aureus

• Published in: The Journal of infectious diseases Vol. 208; no. 1; pp. 83 - 91
• Main Authors: Diaz, Lorena, Kontoyiannis, Dimitrios P., Panesso, Diana, Albert, Nathaniel D., Singh, Kavindra V., Tran, Truc T., Munita, Jose M., Murray, Barbara E., Arias, Cesar A.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.07.2013
• Subjects: Acetamides - pharmacology; Animal models; Animals; Anti-Bacterial Agents - pharmacology; Antibiotics; BACTERIA; Bacteriology; Biological and medical sciences; Disease Models, Animal; Dosage; Dose-Response Relationship, Drug; Drosophila; Drosophila melanogaster - drug effects; Drosophila melanogaster - microbiology; Drug design; Drug Resistance, Bacterial; Female; Fundamental and applied biological sciences. Psychology; Infections; Infectious diseases; Linezolid; Major and Brief Reports; Medical sciences; Mice; Mice, Inbred ICR; Microbiology; Miscellaneous; Oxazolidinones - pharmacology; Peritonitis; Resistance mechanisms; Staphylococcal Infections - drug therapy; Staphylococcus aureus; Staphylococcus aureus - drug effects; Virulence; Linezolid; Insecta; Mechanism; Drosophilidae; Infection; Resistance; Antibiotic; Arthropoda; Oxazolidinone derivative; Bacteria; Micrococcales; Micrococcaceae; Models; Protein synthesis inhibitor; Invertebrata; Antibacterial agent; Oxazole derivatives; Drosophila melanogaster; Diptera; Oxazolidinedione derivatives; Staphylococcus aureus; linezolid; cfr; resistance
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jit138

Background. Mini-host models are simple experimental systems to study host-pathogen interactions. We adapted a Drosophila melanogaster infection model to evaluate the in vivo effect of different mechanisms of linezolid (LNZ) resistance in Staphylococcus aureus. Methods. Fly survival was evaluated after infection with LNZ-resistant S. aureus strains NRS119 (which has mutations in 23S ribosomal RNA [rRNA]), CM-05 and 004-737X (which carry cfr), LNZ-susceptible derivatives of CM-05 and 004-737X (which lack cfr), and ATCC 29213 (an LNZ-susceptible control). Flies were then fed food mixed with LNZ (concentration, 15—500 μg/mL). Results were compared to those in mouse peritonitis, using LNZ via oral gavage at 80 and 120 mg/kg every 12 hours. Results. LNZ at 500 μg/mL in fly food protected against all strains, while concentrations of 15—250 μg/mL failed to protect against NRS119 (survival, 1.6%—20%). An in vivo effect of cfr was only detected at concentrations of 30 and 15 μg/mL. In the mouse peritonitis model, LNZ (at doses that mimic human pharmacokinetics) protected mice from challenge with the cfr+ 004-737X strain but was ineffective against the NRS119 strain, which carried 23S rRNA mutations. Conclusions. The fly model offers promising advantages to dissect the in vivo effect of LNZ resistance in S. aureus, and findings from this model appear to be concordant with those from the mouse peritonitis model.