Bis(diphenylphosphino)amines-containing ruthenium cymene complexes as potential anti-Mycobacterium tuberculosis agents

Silva, Juliana P. da; Silva, Isabel Cristiane da; Pavan, Fernando Rogério; Back, Davi F.; Araujo, Márcio P. de

doi:10.1016/j.jinorgbio.2017.04.008

Cited by 13 publications

(4 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The strains used were from the collection of the Clinical Mycobacteriology and Mycology Laboratories of the School of Pharmaceutical Sciences, UNESP. M. tuberculosis was cultured on Middlebrook 7H9 broth (Difco) supplemented with 10% OADC enrichment (dextrose, albumin, and catalase — BBL/Becton-Dickinson), incubated for 10 days at 37°C at 5% CO 2, and the P. brasiliensis strain was incubated in Fava-Netto medium at 37°C for 4 days ( Fava Netto, 1976 ; da Silva et al., 2017 ).…”

Section: Methodsmentioning

confidence: 99%

“…Then, 30 μL of 0.01% resazurin (Sigma-Aldrich ® ) was added to each well and incubated at 37°C for 24 h. The fluorescence was measured at wavelengths of 530 and 590 nm, for excitation and emission filters, respectively, and read in a cell imaging system, Cytation 3 (Biotek ® ). The assay was performed in triplicate in independent experiments ( Palomino et al., 2002 ; da Silva et al., 2017 ).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Mycobacterium tuberculosis and Paracoccidioides brasiliensis Formation and Treatment of Mixed Biofilm In Vitro

Medina-Alarcón

Silva

Ferin

et al. 2021

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

Co-infection of Mycobacterium tuberculosis and Paracoccidioides brasiliensis, present in 20% in Latin America, is a public health problem due to a lack of adequate diagnosis. These microorganisms are capable of forming biofilms, mainly in immunocompromised patients, which can lead to death due to the lack of effective treatment for both diseases. The present research aims to show for the first time the formation of mixed biofilms of M. tuberculosis and P. brasiliensis (Pb18) in vitro, as well as to evaluate the action of 3’hydroxychalcone (3’chalc) -loaded nanoemulsion (NE) (NE3’chalc) against monospecies and mixed biofilms, the formation of mixed biofilms of M. tuberculosis H37Rv (ATCC 27294), 40Rv (clinical strains) and P. brasiliensis (Pb18) (ATCC 32069), and the first condition of formation (H37Rv +Pb18) and (40Rv + Pb18) and second condition of formation (Pb18 + H37Rv) with 45 days of total formation time under both conditions. The results of mixed biofilms (H37Rv + Pb18) and (40Rv + Pb18), showed an organized network of M. tuberculosis bacilli in which P. brasiliensis yeasts are connected with a highly extracellular polysaccharide matrix. The (Pb18 + H37Rv) showed a dense biofilm with an apparent predominance of P. brasiliensis and fragments of M. tuberculosis. PCR assays confirmed the presence of the microorganisms involved in this formation. The characterization of NE and NE3’chalc displayed sizes from 145.00 ± 1.05 and 151.25 ± 0.60, a polydispersity index (PDI) from 0.20± 0.01 to 0.16± 0.01, and zeta potential -58.20 ± 0.92 mV and -56.10 ± 0.71 mV, respectively. The atomic force microscopy (AFM) results showed lamellar structures characteristic of NE. The minimum inhibitory concentration (MIC) values of 3’hidroxychalcone (3’chalc) range from 0.97- 7.8 µg/mL and NE3’chalc from 0.24 - 3.9 µg/mL improved the antibacterial activity when compared with 3’chalc-free, no cytotoxicity. Antibiofilm assays proved the efficacy of 3’chalc-free incorporation in NE. These findings contribute to a greater understanding of the formation of M. tuberculosis and P. brasiliensis in the mixed biofilm. In addition, the findings present a new possible NE3’chalc treatment alternative for the mixed biofilms of these microorganisms, with a high degree of relevance due to the lack of other treatments for these comorbidities.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Mycobacterium tuberculosis and Paracoccidioides brasiliensis Formation and Treatment of Mixed Biofilm In Vitro

Medina-Alarcón

Silva

Ferin

et al. 2021

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

show abstract

“…In the antimicrobial mechanism against Mtb, a crucial role appeared exerted by the basicity of the amines, which can affect the donor ability of the P-N-P ligands [117]. (N-N), they appeared the most active [118][119][120].…”

Section: Antibiotic Metal Complexes In Mtb Treatmentmentioning

confidence: 99%

Metal–Peptide Complexes as Promising Antibiotics to Fight Emerging Drug Resistance: New Perspectives in Tuberculosis

Natale

Benedictis

et al. 2020

Antibiotics

View full text Add to dashboard Cite

In metal-peptide interactions, cations form stable complexes through bonds with coordinating groups as side chains of amino acids. These compounds, among other things, exert a wide variety of antimicrobial activities through structural changes of peptides upon metal binding and redox chemistry. They exhibit different mechanisms of action (MOA), including the modification of DNA/RNA, protein and cell wall synthesis, permeabilization and modulation of gradients of cellular membranes. Nowadays, the large increase in antibiotic resistance represents a crucial problem to limit progression at the pandemic level of the diseases that seemed nearly eradicated, such as tuberculosis (Tb). Mycobacterium tuberculosis (Mtb) is intrinsically resistant to many antibiotics due to chromosomal mutations which can lead to the onset of novel strains. Consequently, the maximum pharmaceutical effort should be focused on the development of new therapeutic agents and antimicrobial peptides can represent a valuable option as a copious source of potential bioactive compounds. The introduction of a metal center can improve chemical diversity and hence specificity and bioavailability while, in turn, the coordination to peptides of metal complexes can protect them and enhance their poor water solubility and air stability: the optimization of these parameters is strictly required for drug prioritization and to obtain potent inhibitors of Mtb infections with novel MOAs. Here, we present a panoramic review of the most recent findings in the field of metal complex-peptide conjugates and their delivery systems with the potential pharmaceutical application as novel antibiotics in Mtb infections.

show abstract

“…Others reported antitubercular activity for ammines of Ru(II) isoniazid complexes with good MIC values (approximately 0.88 μg/mL), and a theoretical correlation between anti-TB activity and stability of isonicotinoyl radical, not the electrochemical potential of the metal center, was proposed (Aguiar et al, 2015 ). Other ruthenium-based complexes with and without isoniazid bound have been reported to exhibit anti-TB activity (Pavan et al, 2011 ; Garner et al, 2017 ; Silva et al, 2017 ; Smith et al, 2017 ).…”

Section: Developing New Pharmacological Strategies Using Metalsmentioning

confidence: 99%

Is IQG-607 a Potential Metallodrug or Metallopro-Drug With a Defined Molecular Target in Mycobacterium tuberculosis?

et al. 2018

View full text Add to dashboard Cite

The emergence of strains of Mycobacterium tuberculosis resistant to isoniazid (INH) has underscored the need for the development of new anti-tuberculosis agents. INH is activated by the mycobacterial katG-encoded catalase-peroxidase, forming an acylpyridine fragment that is covalently attached to the C4 of NADH. This isonicotinyl-NAD adduct inhibits the activity of 2-trans-enoyl-ACP(CoA) reductase (InhA), which plays a role in mycolic acid biosynthesis. A metal-based INH analog, Na3[FeII(CN)5(INH)]·4H2O, IQG-607, was designed to have an electronic redistribution on INH moiety that would lead to an intramolecular electron transfer to bypass KatG activation. HPLC and EPR studies showed that the INH moiety can be oxidized by superoxide or peroxide yielding similar metabolites and isonicotinoyl radical only when associated to IQG-607, thereby supporting redox-mediated drug activation as a possible mechanism of action. However, IQG-607 was shown to inhibit the in vitro activity of both wild-type and INH-resistant mutant InhA enzymes in the absence of KatG activation. IQG-607 given by the oral route to M. tuberculosis-infected mice reduced lung lesions. Experiments using early and late controls of infection revealed a bactericidal activity for IQG-607. HPLC and voltammetric methods were developed to quantify IQG-607. Pharmacokinetic studies showed short half-life, high clearance, moderate volume of distribution, and low oral bioavailability, which was not altered by feeding. Safety and toxic effects of IQG-607 after acute and 90-day repeated oral administrations in both rats and minipigs showed occurrence of mild to moderate toxic events. Eight multidrug-resistant strains (MDR-TB) were resistant to IQG-607, suggesting an association between katG mutation and increasing MIC values. Whole genome sequencing of three spontaneous IQG-607-resistant strains harbored katG gene mutations. MIC measurements and macrophage infection experiments with a laboratorial strain showed that katG mutation is sufficient to confer resistance to IQG-607 and that the macrophage intracellular environment cannot trigger the self-activation mechanism. Reduced activity of IQG-607 against an M. tuberculosis strain overexpressing S94A InhA mutant protein suggested both the need for KatG activation and InhA as its target. Further efforts are suggested to be pursued toward attempting to translate IQG-607 into a chemotherapeutic agent to treat tuberculosis.

show abstract

Bis(diphenylphosphino)amines-containing ruthenium cymene complexes as potential anti-Mycobacterium tuberculosis agents

Cited by 13 publications

References 49 publications

Mycobacterium tuberculosis and Paracoccidioides brasiliensis Formation and Treatment of Mixed Biofilm In Vitro

Mycobacterium tuberculosis and Paracoccidioides brasiliensis Formation and Treatment of Mixed Biofilm In Vitro

Metal–Peptide Complexes as Promising Antibiotics to Fight Emerging Drug Resistance: New Perspectives in Tuberculosis

Is IQG-607 a Potential Metallodrug or Metallopro-Drug With a Defined Molecular Target in Mycobacterium tuberculosis?

Contact Info

Product

Resources

About