Deadly mould strains highly likely to acquire resistance to new drugs

Scientists have identified strains of one of the world’s most dangerous fungal pathogens, already resistant to our most effective antifungal drugs,  which are also 5-times more likely to acquire resistance to desperately needed new treatments in development. 

The study – led by two University of Manchester researchers and published in Nature Communications – significantly advances our understanding of how Aspergillus fumigatus rapidly develops drug resistance.

 The mould, found in soil, composts, and decaying vegetation, is potentially deadly to people with a range of health conditions including those with weakened immune systems and respiratory problems.

Millions of people develop invasive and chronic aspergillosis infections around the world every year, with mortality rates ranging between 30% to 90%.

Only three classes of antifungal drugs available to treat disease, and only one class, the azoles, is suitable for long-term oral administration.

Resistance to azoles is spreading due to the use of a class of fungicides in agriculture, known as the DMIs. Resistance can double the risk of mortality from invasive aspergillosis.

According to the study funded by The Wellcome Trust, strains resistant to azoles are over five times more likely to acquire resistance to new treatments currently in clinical trials. 

The study follows previous research by the team showing how an agricultural fungicide called ipflufenoquin- currently under consideration by authorities worldwide – could have a devastating effect on a new drug, olorofim, currently being trialled to treat Aspergillus fumigatus infections. 

F2G Ltd – a spin out company from The University of Manchester – invested more than £250 million over 20 years in the development of olorofim, which is in late-stage clinical trials and aims to be clinically deployed within the next few years. 

Because olorofim works against azole resistant infections, it could save many lives of affected patients. 

However, ipflufenoquin, could severely impact the new drug because it has the same biological target and kills the fungi the same way as olorofim. 

Co-author Dr Michael Bottery from The University of Manchester said: “Our discovery, coupled with our previous research on the impact of an agrochemical on antifungal resistance, highlights the urgent need for innovative strategies to combat the growing public health threat of antifungal resistance. 

“Aspergillus fumigatus produces billions of spores. Even slightly elevated rates of mutation mean it is highly likely resistant mutants will arise.” 

By exposing billions of spores from genetically different natural strains of Aspergillus fumigatus to a range of drugs they accelerated evolution in the lab to predict how likely it was for resistance to evolve. 

Strains that evolve faster, they found,  were also the ones already resistant to azoles. These strains had genetic changes in genes that control the fungus’s system which repairs mutated DNA  –  known as the mismatch repair system. 

By using CRISPR-Cas9 to reproduce these variants in the lab, they were able to directly link the changes in the mismatch repair system with the ability of Aspergillus fumigatus to evolve resistance to new drugs. 

Co-author Prof. Michael Bromley from The University of Manchester said: “Specific strains of Aspergillus fumigatus are resistant to azoles, the only effective long-term treatment for chronic aspergillosis.

“But these strains also have elevated mutation rates due to changes in their DNA mismatch repair system – the fungus’s system which repairs errors in its DNA.

“This means that isolates that are already resistant to our first line treatments could develop resistance to new drugs 5 times faster than drug resistant isolates, potentially leading to strains that are resistant to all antifungal medications.”

The  paper “Elevated mutation rates in multi-azole resistant Aspergillus fumigatus drive rapid evolution of antifungal resistance,” to be published in in Nature Communications, is published in Nature Communications.