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Mononuclear ruthenium(ii) theranostic complexes that function as broad-spectrum antimicrobials in therapeutically resistant pathogens through interaction with DNA.

ABSTRACT: Six luminescent, mononuclear ruthenium(ii) complexes based on the tetrapyridophenazine (tpphz) and dipyridophenazine (dppz) ligands are reported. The therapeutic activities of the complexes against Gram-negative bacteria (E. coli, A. baumannii, P. aeruginosa) and Gram-positive bacteria (E. faecalis and S. aureus) including pathogenic multi- and pan-drug resistant strains were assessed. Estimated minimum inhibitory and bactericidal concentrations show the activity of the lead compound is comparable to ampicillin and oxacillin in therapeutically sensitive strains and this activity was retained in resistant strains. Unlike related dinuclear analogues the lead compound does not damage bacterial membranes but is still rapidly taken up by both Gram-positive and Gram-negative bacteria in a glucose independent manner. Direct imaging of the complexes through super-resolution nanoscopy and transmission electron microscopy reveals that once internalized the complexes' intracellular target for both Gram-negative and Gram-positive strains is bacterial DNA. Model toxicity screens showed the compound is non-toxic to Galleria mellonella even at exposure concentrations that are orders of magnitude higher than the bacterial MIC.

SUBMITTER: Smitten KL

PROVIDER: S-EPMC8163430 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Mononuclear ruthenium(ii) theranostic complexes that function as broad-spectrum antimicrobials in therapeutically resistant pathogens through interaction with DNA.

Smitten Kirsty L KL Thick Eleanor J EJ Southam Hannah M HM Bernardino de la Serna Jorge J Foster Simon J SJ Thomas Jim A JA

Chemical science 20200730 33

Six luminescent, mononuclear ruthenium(ii) complexes based on the tetrapyridophenazine (tpphz) and dipyridophenazine (dppz) ligands are reported. The therapeutic activities of the complexes against Gram-negative bacteria (E. coli, A. baumannii, P. aeruginosa) and Gram-positive bacteria (E. faecalis and S. aureus) including pathogenic multi- and pan-drug resistant strains were assessed. Estimated minimum inhibitory and bactericidal concentrations show the activi ...[more]

PMID: 34123136

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Project description:Invasive fungal infections due to Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans constitute a substantial threat to hospitalized immunocompromised patients. Further, the presence of drug-recalcitrant biofilms on medical devices and emergence of drug-resistant fungi, such as Candida auris, introduce treatment challenges with current antifungal drugs. Worse, currently there is no approved drug capable of obviating preformed biofilms, which increase the chance of infection relapses. Here, we screened a small-molecule New Prestwick Chemical Library, consisting of 1,200 FDA-approved off-patent drugs against C. albicans, C. auris, and A. fumigatus, to identify those that inhibit growth of all three pathogens. Inhibitors were further prioritized for their potency against other fungal pathogens and their ability to kill preformed biofilms. Our studies identified the bis-biguanide alexidine dihydrochloride (AXD) as a drug with the highest antifungal and antibiofilm activity against a diverse range of fungal pathogens. Finally, AXD significantly potentiated the efficacy of fluconazole against biofilms, displayed low mammalian cell toxicity, and eradicated biofilms growing in mouse central venous catheters in vivo, highlighting its potential as a pan-antifungal drug.IMPORTANCE The prevalence of fungal infections has seen a rise in the past decades due to advances in modern medicine leading to an expanding population of device-associated and immunocompromised patients. Furthermore, the spectrum of pathogenic fungi has changed, with the emergence of multidrug-resistant strains such as C. auris High mortality related to fungal infections points to major limitations of current antifungal therapy and an unmet need for new antifungal drugs. We screened a library of repurposed FDA-approved inhibitors to identify compounds with activities against a diverse range of fungi in varied phases of growth. The assays identified alexidine dihydrochloride (AXD) to have pronounced antifungal activity, including against preformed biofilms, at concentrations lower than mammalian cell toxicity. AXD potentiated the activity of fluconazole and amphotericin B against Candida biofilms in vitro and prevented biofilm growth in vivo Thus, AXD has the potential to be developed as a pan-antifungal, antibiofilm drug.

Project description:Importance:Broad-spectrum antibiotics are recommended for all patients with suspected sepsis to minimize the risk of undertreatment. However, little is known regarding the net prevalence of antibiotic-resistant pathogens across all patients with community-onset sepsis or the outcomes associated with unnecessarily broad empiric treatment. Objective:To elucidate the epidemiology of antibiotic-resistant pathogens and the outcomes associated with both undertreatment and overtreatment in patients with culture-positive community-onset sepsis. Design, Setting, and Participants:This cohort study included 17 430 adults admitted to 104 US hospitals between January 2009 and December 2015 with sepsis and positive clinical cultures within 2 days of admission. Data analysis took place from January 2018 to December 2019. Exposures:Inadequate empiric antibiotic therapy (ie, ≥1 pathogen nonsusceptible to all antibiotics administered on the first or second day of treatment) and unnecessarily broad empiric therapy (ie, active against methicillin-resistant Staphylococcus aureus [MRSA]; vancomycin-resistant Enterococcus [VRE]; ceftriaxone-resistant gram-negative [CTX-RO] organisms, including Pseudomonas aeruginosa; or extended-spectrum β-lactamase [ESBL] gram-negative organisms when none of these were isolated). Main Outcomes and Measures:Prevalence and empiric treatment rates for antibiotic-resistant organisms and associations of inadequate and unnecessarily broad empiric therapy with in-hospital mortality were assessed, adjusting for baseline characteristics and severity of illness. Results:Of 17 430 patients with culture-positive community-onset sepsis (median [interquartile range] age, 69 [57-81] years; 9737 [55.9%] women), 2865 (16.4%) died in the hospital. The most common culture-positive sites were urine (9077 [52.1%]), blood (6968 [40.0%]), and the respiratory tract (2912 [16.7%]). The most common pathogens were Escherichia coli (5873 [33.7%]), S aureus (3706 [21.3%]), and Streptococcus species (2361 [13.5%]). Among 15 183 cases in which all antibiotic-pathogen susceptibility combinations could be calculated, most (12 398 [81.6%]) received adequate empiric antibiotics. Empiric therapy targeted resistant organisms in 11 683 of 17 430 cases (67.0%; primarily vancomycin and anti-Pseudomonal β-lactams), but resistant organisms were uncommon (MRSA, 2045 [11.7%]; CTX-RO, 2278 [13.1%]; VRE, 360 [2.1%]; ESBLs, 133 [0.8%]). The net prevalence for at least 1 resistant gram-positive organism (ie, MRSA or VRE) was 13.6% (2376 patients), and for at least 1 resistant gram-negative organism (ie, CTX-RO, ESBL, or CRE), it was 13.2% (2297 patients). Both inadequate and unnecessarily broad empiric antibiotics were associated with higher mortality after detailed risk adjustment (inadequate empiric antibiotics: odds ratio, 1.19; 95% CI, 1.03-1.37; P = .02; unnecessarily broad empiric antibiotics: odds ratio, 1.22; 95% CI, 1.06-1.40; P = .007). Conclusions and Relevance:In this study, most patients with community-onset sepsis did not have resistant pathogens, yet broad-spectrum antibiotics were frequently administered. Both inadequate and unnecessarily broad empiric antibiotics were associated with higher mortality. These findings underscore the need for better tests to rapidly identify patients with resistant pathogens and for more judicious use of broad-spectrum antibiotics for empiric sepsis treatment.

Dataset Information

Mononuclear ruthenium(ii) theranostic complexes that function as broad-spectrum antimicrobials in therapeutically resistant pathogens through interaction with DNA.

Publications

Mononuclear ruthenium(ii) theranostic complexes that function as broad-spectrum antimicrobials in therapeutically resistant pathogens through interaction with DNA.

Similar Datasets

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