Metal Complexes as Antifungals? From a Crowd-Sourced Compound Library to the First In Vivo Experiments.

There are currently fewer than 10 antifungal drugs in clinical development, but new fungal strains that are resistant to most current antifungals are spreading rapidly across the world. To prevent a second resistance crisis, new classes of antifungal drugs are urgently needed. Metal complexes have proven to be promising candidates for novel antibiotics, but so far, few compounds have been explored for their potential application as antifungal agents. In this work, we report the evaluation of 1039 metal-containing compounds that were screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD). We show that 20.9% of all metal compounds tested have antimicrobial activity against two representative Candida and Cryptococcus strains compared with only 1.1% of the >300,000 purely organic molecules tested through CO-ADD. We identified 90 metal compounds (8.7%) that show antifungal activity while not displaying any cytotoxicity against mammalian cell lines or hemolytic properties at similar concentrations. The structures of 21 metal complexes that display high antifungal activity (MIC ≤1.25 µM) are discussed and evaluated further against a broad panel of yeasts. Most of these have not been previously tested for antifungal activity. Eleven of these metal complexes were tested for toxicity in the Galleria mellonella moth larva model, revealing that only one compound showed signs of toxicity at the highest injected concentration. Lastly, we demonstrated that the organo-Pt(II) cyclooctadiene complex Pt1 significantly reduces fungal load in an in vivo G. mellonella infection model. These findings showcase that the structural and chemical diversity of metal-based compounds can be an invaluable tool in the development of new drugs against infectious diseases.

Host transmission dynamics of first- and third-stage Angiostrongylus cantonensis larvae in Bullastra lessoni.

Given the importance of angiostrongyliasis as an emerging infectious disease of humans, companion animals, and wildlife, the current study focused on the transmission dynamics of first- and third-stage larvae of the parasitic nematode, Angiostrongylus cantonensis. The migration of infective larvae and their subsequent distribution within the Lymnaeidae snail, Bullastra lessoni, were investigated over time using microscopic examination of histological sections and fresh tissue. Snails were divided into four anatomical regions: (i) anterior and (ii) posterior cephalopedal masses, (iii) mantle skirt and (iv) visceral mass. The viability of free-swimming third-stage larvae, after their release from snail tissues, was evaluated in vitro by propidium iodide staining and infectivity by in vivo infection of Wistar rats. Snails were sequentially dissected over time to assess the number and anatomical distribution of larvae within each snail and hence infer their migration pathway. Herein, ongoing larval migratory activity was detected over 28 days post-infection. A comparison of infection rates and the larval distribution within the four designated snail regions demonstrated a significant relationship between anatomical region and density of infective larvae, with larvae mostly distributed in the anterior cephalopedal mass (43.6 ± 10.8%) and the mantle skirt (33.0 ± 8.8%). Propidium iodide staining showed that free-swimming third-stage larvae retained viability for between 4 and 8 weeks when stored under laboratory conditions. In contrast to viability, larval infectivity in rats remained for up to 2 weeks only. Knowledge gained from the current work could provide information on the development of new approaches to controlling the transmission of this parasite.

Further studies of neuroangiostrongyliasis (rat lungworm disease) in Australian dogs: 92 new cases (2010-2020) and results for a novel, highly sensitive qPCR assay.

The principal aim of this study was to optimize the diagnosis of canine neuroangiostrongyliasis (NA). In total, 92 cases were seen between 2010 and 2020. Dogs were aged from 7 weeks to 14 years (median 5 months), with 73/90 (81%) less than 6 months and 1.7 times as many males as females. The disease became more common over the study period. Most cases (86%) were seen between March and July. Cerebrospinal fluid (CSF) was obtained from the cisterna magna in 77 dogs, the lumbar cistern in f5, and both sites in 3. Nucleated cell counts for 84 specimens ranged from 1 to 146 150 cells µL-1 (median 4500). Percentage eosinophils varied from 0 to 98% (median 83%). When both cisternal and lumbar CSF were collected, inflammation was more severe caudally. Seventy-three CSF specimens were subjected to enzyme-linked immunosorbent assay (ELISA) testing for antibodies against A. cantonensis; 61 (84%) tested positive, titres ranging from <100 to ⩾12 800 (median 1600). Sixty-one CSF specimens were subjected to real-time quantitative polymerase chain reaction (qPCR) testing using a new protocol targeting a bioinformatically-informed repetitive genetic target; 53/61 samples (87%) tested positive, CT values ranging from 23.4 to 39.5 (median 30.0). For 57 dogs, it was possible to compare CSF ELISA serology and qPCR. ELISA and qPCR were both positive in 40 dogs, in 5 dogs the ELISA was positive while the qPCR was negative, in 9 dogs the qPCR was positive but the ELISA was negative, while in 3 dogs both the ELISA and qPCR were negative. NA is an emerging infectious disease of dogs in Sydney, Australia.

The Effect of Different Carbapenem Antibiotics (Ertapenem, Imipenem/Cilastatin, and Meropenem) on Serum Valproic Acid Concentrations.

BACKGROUND: Carbapenem antibiotics (CBPMs) may significantly reduce the serum concentration of valproic acid (VPA), but the extent of this effect among various CBPMs is unknown. This study compared the extent and onset of the interactions among ertapenem, imipenem/cilastatin, and meropenem. METHODS: A 5-year retrospective study was performed. Hospitalized patients over 18 years old who received VPA and a CBPM concurrently were enrolled via the pharmacy computer system. Patients who lacked VPA serum concentration measurements before or during CBPMs' use, had concurrent medication(s) that might interfere with VPA metabolism, or had a history of liver cirrhosis were excluded. Total VPA serum concentrations before and during CBPMs' use and after its discontinuation were recorded, and differences among various CBPMs were analyzed. RESULTS: Fifty-two patients were included in this analysis. Irrespective of the route of administration, VPA serum concentrations were subtherapeutic in 90% of the subjects during CBPMs' use. There was a significant decrease (P < 0.001) in VPA serum concentrations during the use of CBPMs: 72% ± 17%, 42% ± 22%, and 67% ± 19% in the ertapenem (N = 9), imipenem/cilastatin (N = 17), and meropenem (N = 26) groups, respectively. The effect of ertapenem and meropenem on VPA was significantly more expressed than that of imipenem/cilastatin (P < 0.005). The onset of this drug interaction occurred within 24 hours of CBPMs' administration, and VPA serum concentrations returned to 90% of baseline within 7 days of CBPMs' discontinuation along with a 20% increase in VPA dose. Increasing VPA dose during the use of ertapenem or meropenem did not result in elevating VPA serum concentrations to therapeutic levels during the combined therapy period. CONCLUSIONS: CBPMs reduced VPA serum concentration within 24 hours of administration by approximately 60%. Ertapenem and meropenem had a greater effect on VPA serum concentration than imipenem/cilastatin. Because of the dramatic reduction of VPA serum concentration during CBPMs' use, concomitant use of VPA and CBPMs should be avoided.