A C∧S-Cyclometallated Gold(III) Complex as a Novel Antibacterial Candidate Against Drug-Resistant Bacteria
The worldwide emergence and spread of infections caused by multidrug-resistant bacteria endangers the efficacy of current antibiotics in the clinical setting. The lack of new antibiotics in the pipeline points to the need of developing new strategies. Recently, gold-based drugs are being repurposed...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-03-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmicb.2022.815622/full |
| _version_ | 1818906855879999488 |
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| author | Carlos Ratia Virginio Cepas Raquel Soengas Yolanda Navarro María Velasco-de Andrés María José Iglesias Francisco Lozano Francisco Lozano Francisco Lozano Fernando López-Ortiz Sara M. Soto |
| author_facet | Carlos Ratia Virginio Cepas Raquel Soengas Yolanda Navarro María Velasco-de Andrés María José Iglesias Francisco Lozano Francisco Lozano Francisco Lozano Fernando López-Ortiz Sara M. Soto |
| author_sort | Carlos Ratia |
| collection | DOAJ |
| description | The worldwide emergence and spread of infections caused by multidrug-resistant bacteria endangers the efficacy of current antibiotics in the clinical setting. The lack of new antibiotics in the pipeline points to the need of developing new strategies. Recently, gold-based drugs are being repurposed for antibacterial applications. Among them, gold(III) complexes have received increasing attention as metal-based anticancer agents. However, reports on their antibacterial activity are scarce due to stability issues. The present work demonstrates the antibacterial activity of the gold(III) complex 2 stabilized as C∧S-cycloaurated containing a diphenylphosphinothioic amide moiety, showing minimum inhibitory concentration (MIC) values that ranged from 4 to 8 and from 16 to 32 mg/L among Gram-positive and Gram-negative multidrug-resistant (MDR) pathogens, respectively. Complex 2 has a biofilm inhibitory activity of only two to four times than its MIC. We also describe for the first time a potent antibacterial synergistic effect of a gold(III) complex combined with colistin, showing a bactericidal effect in less than 2 h; confirming the role of the outer membrane as a permeability barrier. Complex 2 shows a low rate of internalization in Staphylococcus aureus and Acinetobacter baumannii; it does not interact with replication enzymes or efflux pumps, causes ultrastructural damages in both membrane and cytoplasmic levels, and permeabilizes the bacterial membrane. Unlike control antibiotics, complex 2 did not generate resistant mutants in 30-day sequential cultures. We detected lower cytotoxicity in a non-tumoral THLE-2 cell line (IC50 = 25.5 μM) and no acute toxicity signs in vivo after an i.v. 1-mg/kg dose. The characterization presented here reassures the potential of complex 2 as a new chemical class of antimicrobial agents. |
| first_indexed | 2024-12-19T21:45:52Z |
| format | Article |
| id | doaj.art-69512af151854bfbac74475eaf108af1 |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-12-19T21:45:52Z |
| publishDate | 2022-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-69512af151854bfbac74475eaf108af12022-12-21T20:04:32ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2022-03-011310.3389/fmicb.2022.815622815622A C∧S-Cyclometallated Gold(III) Complex as a Novel Antibacterial Candidate Against Drug-Resistant BacteriaCarlos Ratia0Virginio Cepas1Raquel Soengas2Yolanda Navarro3María Velasco-de Andrés4María José Iglesias5Francisco Lozano6Francisco Lozano7Francisco Lozano8Fernando López-Ortiz9Sara M. Soto10ISGlobal, Hospital Clínic, Universitat de Barcelona, Barcelona, SpainISGlobal, Hospital Clínic, Universitat de Barcelona, Barcelona, SpainÁrea de Química Orgánica, Centro de Investigación CIAIMBITAL, Universidad de Almería, Almería, SpainÁrea de Química Orgánica, Centro de Investigación CIAIMBITAL, Universidad de Almería, Almería, SpainImmunoreceptors del Sistema Innat i Adaptatiu, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, SpainÁrea de Química Orgánica, Centro de Investigación CIAIMBITAL, Universidad de Almería, Almería, SpainImmunoreceptors del Sistema Innat i Adaptatiu, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, SpainServei d’Immunologia, Centre de Diagnòstic Biomèdic, Hospital Clínic de Barcelona, Barcelona, SpainDepartament de Biomedicina, Universitat de Barcelona, Barcelona, SpainÁrea de Química Orgánica, Centro de Investigación CIAIMBITAL, Universidad de Almería, Almería, SpainISGlobal, Hospital Clínic, Universitat de Barcelona, Barcelona, SpainThe worldwide emergence and spread of infections caused by multidrug-resistant bacteria endangers the efficacy of current antibiotics in the clinical setting. The lack of new antibiotics in the pipeline points to the need of developing new strategies. Recently, gold-based drugs are being repurposed for antibacterial applications. Among them, gold(III) complexes have received increasing attention as metal-based anticancer agents. However, reports on their antibacterial activity are scarce due to stability issues. The present work demonstrates the antibacterial activity of the gold(III) complex 2 stabilized as C∧S-cycloaurated containing a diphenylphosphinothioic amide moiety, showing minimum inhibitory concentration (MIC) values that ranged from 4 to 8 and from 16 to 32 mg/L among Gram-positive and Gram-negative multidrug-resistant (MDR) pathogens, respectively. Complex 2 has a biofilm inhibitory activity of only two to four times than its MIC. We also describe for the first time a potent antibacterial synergistic effect of a gold(III) complex combined with colistin, showing a bactericidal effect in less than 2 h; confirming the role of the outer membrane as a permeability barrier. Complex 2 shows a low rate of internalization in Staphylococcus aureus and Acinetobacter baumannii; it does not interact with replication enzymes or efflux pumps, causes ultrastructural damages in both membrane and cytoplasmic levels, and permeabilizes the bacterial membrane. Unlike control antibiotics, complex 2 did not generate resistant mutants in 30-day sequential cultures. We detected lower cytotoxicity in a non-tumoral THLE-2 cell line (IC50 = 25.5 μM) and no acute toxicity signs in vivo after an i.v. 1-mg/kg dose. The characterization presented here reassures the potential of complex 2 as a new chemical class of antimicrobial agents.https://www.frontiersin.org/articles/10.3389/fmicb.2022.815622/fullgold(III) antimicrobialcycloaurateMDRMRSAsynergy |
| spellingShingle | Carlos Ratia Virginio Cepas Raquel Soengas Yolanda Navarro María Velasco-de Andrés María José Iglesias Francisco Lozano Francisco Lozano Francisco Lozano Fernando López-Ortiz Sara M. Soto A C∧S-Cyclometallated Gold(III) Complex as a Novel Antibacterial Candidate Against Drug-Resistant Bacteria Frontiers in Microbiology gold(III) antimicrobial cycloaurate MDR MRSA synergy |
| title | A C∧S-Cyclometallated Gold(III) Complex as a Novel Antibacterial Candidate Against Drug-Resistant Bacteria |
| title_full | A C∧S-Cyclometallated Gold(III) Complex as a Novel Antibacterial Candidate Against Drug-Resistant Bacteria |
| title_fullStr | A C∧S-Cyclometallated Gold(III) Complex as a Novel Antibacterial Candidate Against Drug-Resistant Bacteria |
| title_full_unstemmed | A C∧S-Cyclometallated Gold(III) Complex as a Novel Antibacterial Candidate Against Drug-Resistant Bacteria |
| title_short | A C∧S-Cyclometallated Gold(III) Complex as a Novel Antibacterial Candidate Against Drug-Resistant Bacteria |
| title_sort | c∧s cyclometallated gold iii complex as a novel antibacterial candidate against drug resistant bacteria |
| topic | gold(III) antimicrobial cycloaurate MDR MRSA synergy |
| url | https://www.frontiersin.org/articles/10.3389/fmicb.2022.815622/full |
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