Combinatory Effect of Nitroxoline and Gentamicin in the Control of Uropathogenic Enterococci Infections

Author:

Repac Antić Davorka12ORCID,Kovač Bruno3ORCID,Kolenc Marko4,Brčić Karačonji Irena56ORCID,Gobin Ivana1ORCID,Petković Didović Mirna7ORCID

Affiliation:

1. Department of Microbiology and Parasitology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia

2. Department of Clinical Microbiology, Clinical Hospital Center Rijeka, 51000 Rijeka, Croatia

3. Chair of Buildings and Constructional Complexes, Faculty of Civil and Geodetic Engineering, University of Ljubljana, 1000 Ljubljana, Slovenia

4. Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia

5. Division of Toxicology, Institute for Medical Research and Occupational Health, 10000 Zagreb, Croatia

6. Department of Basic Medical Sciences, Faculty of Health Studies, University of Rijeka, 51000 Rijeka, Croatia

7. Department of Medical Chemistry, Biochemistry and Clinical Chemistry, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia

Abstract

Enterococcus faecalis, responsible for a majority of human and nosocomial enterococcal infections, is intrinsically resistant to aminoglycoside antibiotics (such as gentamicin, GEN), which must be used in a combined therapy to be effective. Nitroxoline (NTX) is an old antibiotic, underused for decades, but rediscovered now in an era of growing antibiotic resistance. In this in vitro study, the types of interactions between NTX and GEN on 29 E. faecalis strains were analyzed with an aim to find synergistic antimicrobial and antiadhesion combinations. Transmission electron microscopy (TEM) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) were used to analyze changes in cell morphology and bacterial proteome after monotreatments and combined treatments. The results showed the synergistic effect for six combinations on eight strains, including the ATCC29212, and an additive effect for most strains. Combinations causing a complete inhibition of adhesion were established. Cell membrane integrity was affected by NTX, while combined NTX/GEN treatment caused dramatic changes in cell morphology. Upregulation of the expression of many proteins was established, with some emerging only after combined treatment. The results strongly imply that NTX has the potential for use in combined therapy with GEN against enterococci and it could further provide a substantial contribution to an ongoing fight against antimicrobial resistance and nosocomial infections.

Funder

University of Rijeka

Publisher

MDPI AG

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