MIMM211- Mycology in a Warming World Lecture 5 2024 PDF

MIMM211- Mycology in a warming world François Le Mauff, PhD (he/his) 1  Please download and install the Slido app on all computers you use Join at slido.com #1064842 ⓘ Start presenting to display the...

MIMM211- Mycology in a warming world François Le Mauff, PhD (he/his) 1  Please download and install the Slido app on all computers you use Join at slido.com #1064842 ⓘ Start presenting to display the joining instructions on this slide. Are we ready? 4  Please download and install the Slido app on all computers you use Are we ready? ⓘ Start presenting to display the poll results on this slide. Antifungals, what do we have? 7 Finding a therapeutic target is challenging Fungi possess true nucleus Protein secretory pathway (ER, Golgi) Mitochodrion (like animals) Vacuole (like plants – but no chloroplasts!) Cytoplasmic membrane contains Ergosterol (cholesterol in animals / mix of sterol in plants) 3 main families of antifungal developped: 2 against Ergosterol, 1 against the cell 8 wall  Target 1: Fungal cell wall Incredibly diverse polysaccharide structures all based on chitin Limited amount of drugs and studies 9 https://doi.org/10.1128/microbiolspec.funk-0035-2016  Echinocandins – Cell wall inhibitors Newest family of molecules approved by the FDA (2001) Caspofungin First line of defense against yeast invasive infections → Fungicidal effect on most of them Fungistatic in molds 10  Target 2: Ergosterol Ergosterol insure fungal plasma membrane fluidity. 2 main families of antifungals targets this molecule: - Polyenes - Azoles doi: 10.2174/1389557516666160118112103 11  Polyenes – Ergosterol binder Amphotericin B Isolated in the 50’s and are still the antifungal gold standard – broad spectrum activity and low fungal resistance Use in severe cases of invasive infections Important toxicity! Ergosterol VS Cholesterol Maximal dose: 1mg/kg/day over 2 to 4 hours New formulations in development and use https://doi.org/10.3390/jof6040321 12 Azoles – Inhibitor of ergosterol synthesis Synthetic family of molecules developped since the 60’s containing : an imidazole group: or a triazole group: First line of defense against invasive mold infections as generally fungicidal Generally fungistatic against yeast 13  For all drugs, resistance rate is increasing Fungi are creative and resilient. 14 https://doi.org/10.1016/j.fgb.2019.103254  For all drugs, resistance rate is increasing BIOFILMS CAN INCREASE THE RESISTANCE TO A DRUG BY 1000 FOLD 15 https://doi.org/10.1016/j.fgb.2019.103254  Biofilms, important contributor to resistance C. albicans in catheter A. fumigatus on a microscopy coverslip Biofilm: Self made matrix constituted of polysaccharides and proteins 16 DOI 10.1016/j.mib.2006.06.007  Azoles limitations Important rate of resistance development Agricultural use of azoles is a driving source of resistance Direct consequences on medical treatment: 14% of environmental Aspergillus strains resistant to medical azoles in the UK! 7% of spores found in Eastern Himalaya are resistant to at least 1 medical azole!! https://doi.org/10.3389/fcimb.2021.730297 17  Antifungal summary 3 main families of drugs: Echinocandins (2001) Inhibition of β- glucans Resistance is on the rise Polyenes (1950’s) Ergosterol binding Azoles (1960’s) Inhibition of ergosterol synthesis 18 https://doi.org/10.3389/fmicb.2022.911322  Antifungal summary 3 main families of drugs: New molecules are in preclinical and clinical stages. Echinocandins (2001) Inhibition of β- glucans Repeats of the same mistakes are in perspective: Resistance is Ipflufenoquin – approved US EPA 2023 on the rise is able to select for resistant strains (Publication in review) Polyenes (1950’s) Ergosterol binding Azoles (1960’s) Inhibition of ergosterol synthesis 19 https://doi.org/10.3389/fmicb.2022.911322  Please download and install the Slido app on all computers you use What is your main concern? ⓘ Start presenting to display the poll results on this slide.  We are losing our antifungals. More people are getting at risk (more immunosuppressed people). Temperature are rising! Only 6% of fungi can grow at 37°C today, what about tomorrow? We have to deal with new conditions helping fungal dispersion and disease. 21 Report from October 25, 2022 22 3 priority groups of pathogens 23 NBC News Nevada April 2023 24 Candida auris, the rise of a mysterious superbug 2377 cases in 2022 4% Pan-resistance Also resist to classical hospital disinfectants!! 25 Candida auris, the rise of a mysterious superbug Candida auris history Since 2009, Candida auris was reported all the round the world at an alarming rate 26 https://doi.org/10.1016/j.mib.2019.05.008 Candida auris, the rise of a mysterious superbug Candida auris mysterious origin 4 clades suddenly appear around the world in the span of 5 years! Phylogenic studies show an important diversity between the clade (40,000 to 200,000 SNPs) Intra-clade phylogeny shows less than 600 SNPs → It can’t be the same ancestor travelling the world! 27 https://doi.org/10.1016/j.mib.2019.05.008  Please download and install the Slido app on all computers you use What do you think happened? ⓘ Start presenting to display the poll results on this slide.  Candida auris, the rise of a mysterious superbug Lead hypothesis involving: Global warming: Allowing the strain to resist to temperature up to 42°C Ecological niche: - Rich in salt (resistance to up to 10% NaCl) - Rich in antibiotics (resistance to antifungals) - Persistence facilitated on plastic polluants. Intermediate animal reservoir remains to be established. 29 https://doi.org/10.1128/mBio.01397-19.  More superbugs are coming! Trichophyton indotineae epidemic propagation 2021 2023 Origin: Indian subcontinent Multidrug resistant dermatophyte 30 https://doi.org/10.3390/jof8070757 https://doi.org/10.3389/fimmu.2022.1113065 3 priority groups of pathogens 31  Valley fever Dimorphic fungi Coccidioides imitis & C. posadasii Mycelium Spherules & endospores 32  Valley fever Coccidioides right lung cavitary pneumonia with bacterial abscess Erythema multiforme Dimorphic fungi Coccidioides imitis & C. posadasii Symptoms: Pulmonary - Pneumonia like symptoms Dissemination to the skin, lymph nodes, bone, joints, CNS Erythema nodosum Affected groups: 40% of the people inhaling spore will become symptomatic 1-5% dissemination Coccidioides cervical 10x risk AfroAmerican population lymphadenitis 175x risk Filipino population 200 deaths in 2019 in the USA 33 Source: Valley Fever center for Excellence, University of Arizona  Valley fever – medium priority group? Coccidioides sp. spread in region with low humidity and high temperatures MAT: Mean Annual Temperature MAP: Mean Annual Precipitations 35 https://doi.org/10.1029/2019GH000209 Valley fever – medium priority group? Climate change increases the range of Coccidioides sp. enlarging the population at risk of Coccidiomycosis 36 Disaster mycology 37  Unexpected pathogens 2023 A 61 year old male patient from the eastern region of India Profession: Plant mycologist Chondrostereum purpureum No history of diabetes, HIV infection, renal or any chronic disease, immunosuppressive drug intake, or trauma. (D0) with hoarseness of voice, cough, recurrent pharyngitis, fatigue, difficulty in swallowing and anorexia for the last 3 months. (D30) The infection was treated with complete drainage of the pus followed by oral voriconazole for total 60 days (D745) The patient was absolutely fine, no evidence of recurrence 38 Unexpected pathogens 39 Unexpected pathogens Abstract Conclusion Are we ready ? … Not as mush as we should be! Aug 5, 2022 41  I hope you had fun! Please fill up your evaluation sheets, your comments are highly appreciated and valuable!! Contact: [email protected] 42