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A new humanized antibody is effective against pathogenic fungi in vitro.

ABSTRACT: Invasive fungal infections mainly affect patients undergoing transplantation, surgery, neoplastic disease, immunocompromised subjects and premature infants, and cause over 1.5 million deaths every year. The most common fungi isolated in invasive diseases are Candida spp., Cryptococcus spp., and Aspergillus spp. and even if four classes of antifungals are available (Azoles, Echinocandins, Polyenes and Pyrimidine analogues), the side effects of drugs and fungal acquired and innate resistance represent the major hurdles to be overcome. Monoclonal antibodies are powerful tools currently used as diagnostic and therapeutic agents in different clinical contexts but not yet developed for the treatment of invasive fungal infections. In this paper we report the development of the first humanized monoclonal antibody specific for β-1,3 glucans, a vital component of several pathogenic fungi. H5K1 has been tested on C. auris, one of the most urgent threats and resulted efficient both alone and in combination with Caspofungin and Amphotericin B showing an enhancement effect. Our results support further preclinical and clinical developments for the use of H5K1 in the treatment of patients in need.

SUBMITTER: Di Mambro T

PROVIDER: S-EPMC8484667 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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A new humanized antibody is effective against pathogenic fungi in vitro.

Di Mambro Tomas T Vanzolini Tania T Bruscolini Pierpaolo P Perez-Gaviro Sergio S Marra Emanuele E Roscilli Giuseppe G Bianchi Marzia M Fraternale Alessandra A Schiavano Giuditta Fiorella GF Canonico Barbara B Magnani Mauro M

Scientific reports 20210930 1

Invasive fungal infections mainly affect patients undergoing transplantation, surgery, neoplastic disease, immunocompromised subjects and premature infants, and cause over 1.5 million deaths every year. The most common fungi isolated in invasive diseases are Candida spp., Cryptococcus spp., and Aspergillus spp. and even if four classes of antifungals are available (Azoles, Echinocandins, Polyenes and Pyrimidine analogues), the side effects of drugs and fungal acquired and innate resistance repre ...[more]

PMID: 34593880

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Project description:IntroductionAzole resistance has been increasingly reported and become an issue for clinical managements of invasive mycoses. New strategy with combination therapy arises as a valuable and promising alternative option. The aim of the present study is to investigate the in vitro combinational effect of proton pump inhibitors (PPIs) and azoles against pathogenic fungi.MethodsIn vitro interactions of PPIs including omeprazole (OME), lansoprazole (LAN), pantoprazole (PAN), and rabeprazole (RAB), and commonly used azoles including itraconazole (ITC), posaconazole (POS), voriconazole (VRC) and fluconazole (FLC), were investigated via broth microdilution chequerboard procedure adapted from the CLSI M27-A3 and M38-A2. A total of 67 clinically isolated strains, namely 27 strains of Aspergillus spp., 16 strains of Candida spp., and 24 strains of dematiaceous fungi, were studied. C. parapsilosis (ATCC 22019) and A. flavus (ATCC 204304) was included to ensure quality control.ResultsPPIs individually did not exert any significant antifungal activity. The combination of OME with ITC, POS, or VRC showed synergism against 77.6%, 86.6%, and 4% strains of tested pathogenic fungi, respectively, while synergism of OME/FLC was observed in 50% strains of Candida spp. Synergism between PAN and ITC, POS, or VRC was observed against 47.8%, 77.6% and 1.5% strains of tested fungi, respectively, while synergism of PNA/FLC was observed in 50% strains of Candida spp. Synergism of LAN with ITC, POS, or VRC was observed against 86.6%, 86.6%, and 3% of tested strains, respectively, while synergism of LAN/FLC was observed in 31.3% strains of Candida spp. Synergy of the combination of RAB with ITC, POS, or VRC was observed against 25.4%, 64.2%, and 4.5% of tested strains, respectively, while synergism of RAB/FLC was observed in 12.5% of Candida spp.. Among PPIs, synergism was least observed between RAB and triazoles, while among triazoles, synergism was least observed between VRC and PPIs. Among species, synergy was much more frequently observed in Aspergillus spp. and dematiaceous fungi as compared to Candida spp. Antagonism between PPIs with ITC or VRC was occasionally observed in Aspergillus spp. and dematiaceous fungi. It is notable that PPIs combined with azoles showed synergy against azole resistant A. fumigatus, and resulted in category change of susceptibility of ITC and POS against Candida spp.DiscussionThe results suggested that PPIs combined with azoles has the potential to enhance the susceptibilities of azoles against multiple pathogenic fungi and could be a promising strategy to overcome azole resistance issues. However, further investigations are warranted to study the combinational efficacy in more isolates and more species, to investigate the underlying mechanism of interaction and to evaluate the potential for concomitant use of these agents in human.

Project description:Plant rhizosphere soil contains a large number of plant-growth promoting rhizobacteria, which can not only resist the invasion of pathogenic microorganisms and protect plants from damage, but also promote the growth and development of plants. In this study, Pseudomonas aeruginosa strain YY322, isolated and screened from the rhizosphere soil of saffron (Crocus sativus L.), was found through a plate confrontation experiment to show highly effectual and obvious antagonistic activity against the pathogens of saffron, including Fusarium oxysporum, Fusarium solani, Penicillium citreosulfuratum, Penicillium citrinum and Stromatinia gladioli. In addition, the volatile organic compounds of strain YY322 had great antagonistic activity against these pathogens. Observation under a scanning electron microscope and transmission electron microscope reflected that strain YY322 had a significant effect on the hyphae and conidia of F. oxysporum and F. solani. Through the detection of degrading enzymes, it was found that P. aeruginosa can secrete protease and glucanase. The plant growth promoting performance was evaluated, finding that strain YY322 had the functions of dissolving phosphorus, fixing nitrogen, producing siderophore and producing NH3. In addition, whole genome sequencing analysis indicated that the YY322 genome is comprised of a 6,382,345-bp circular chromosome, containing 5809 protein-coding genes and 151 RNA genes. The P. aeruginosa YY322 genome encodes genes related to phenazine (phzABDEFGIMRS), hydrogen cyanide(HCN) (hcnABC), surfactin (srfAA), salicylate (pchA), biofilm formation (flgBCDEFGHIJKL, motAB, efp, hfq), and colonization (minCDE, yjbB, lysC). These results collectively indicated the role of P. aeruginosa YY322 in plant growth enhancement and biocontrol mechanisms. All in all, this study provides a theoretical basis for P. aeruginosa as the PGPR of saffron, paving the way for the subsequent development and utilization of microbial fertilizer.

Project description:Multifunctional drugs have shown great promise in biomedicine. Organisms with antimicrobial and anticancer activity in combination with antioxidant activity need further research. The Red Sea and the Arabian Gulf coasts were randomly sampled to find fungi with multifunctional activity. One hundred strains (98 fungi and 2 lichenized forms) were isolated from 15 locations. One-third of the isolates inhibited clinical bacterial (Staphylococcus aureus, Bacillus subtilis, Vibrio cholerae, Salmonella typhi, S. paratyphi) and fungal pathogens (Talaromycets marneffei, Malassezia globose, Cryptococcus neoformans, Candida albicans, Aspergillus fumigatus) and four cancer cell lines (Hep G2 liver, A-549 lung, A-431skin, MCF 7 breast cancer). Bacterial and cancer inhibition was often accompanied by a high antioxidant activity, as indicated by the principal component analysis (PCA). PCA also indicated that fungal and bacterial pathogens appeared to be inhibited mostly by different marine fungal isolates. Strains with multifunctional activity were found more from the Rea Sea than from the Arabian Gulf coasts. The highest potential for multifunctional drugs were observed for Acremonium sp., Acrocalymma sp., Acrocalymma africana, Acrocalymma medicaginis (activity reported for the first time), Aspergillus sp. Cladosporium oxysporum, Emericellopsis alkaline, Microdochium sp., and Phomopsis glabrae. Lung, skin, and breast cancers were inhibited 85%–97% by Acremonium sp, while most of the isolates showed low inhibition (ca 20%). The highest antifungal activity was observed for Acremonium sp., Diaporthe hubeiensis, Lasiodiplodia theobromae, and Nannizia gypsea. One Acremonium sp. is of particular interest to offer a multifunctional drug; it displayed both antifungal and antibacterial activity combined with high antioxidant activity (DPPH scavenging 97%). A. medicaginis displayed combined antibacterial, anticancer, and antioxidant activity being of high interest. Several genera and some species included strains with both high and low biological activities pointing out the need to study several isolates to find the most efficient strains for biomedical applications.

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A new humanized antibody is effective against pathogenic fungi in vitro.

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A new humanized antibody is effective against pathogenic fungi in vitro.

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