Tag: antimicrobial resistance

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Ignore Antifungal Resistance at Your Peril, Scientists Warn

On By ModernMedia
Candida Auris

Without immediate action, humanity will potentially face further escalation in resistance in fungal disease, a renowned group of scientists from the across the world has warned. The commentary – published in ‘The Lancet’ this week – was coordinated by scientists at The University of Manchester, the Westerdijk Institute and the University of Amsterdam. According to the scientists most fungal pathogens identified by the World Health Organization – accounting for around 3.8 million deaths a year – are either already resistant or rapidly acquiring resistance to antifungal drugs.

The authors argue that the currently narrow focus on bacteria will not fully combat antimicrobial resistance (AMR). September’s United Nations meeting on antimicrobial resistance (AMR) must, they demand, include resistance developed in many fungal pathogens.

Devastating health impacts

Resistance is nowadays the rule rather than the exception for the four currently available antifungal classes, making it difficult – if not impossible – to treat many invasive fungal infections. Fungicide resistant infections include Aspergillus, Candida, Nakaseomyces glabratus, and Trichophyton indotineae, all of which can have devastating health impacts on older or immunocompromised people.

Dr Norman van Rhijn from The University of Manchester coordinated the comment with Professor Ferry Hagen from the University of Amsterdam and the Westerdijk Institute in the Netherlands.

Dr van Rhijn said: “Most people agree that resistant bacterial infections constitute a significant part of the AMR problem. However many drug resistance problems over the past decades have also been the result of invasive fungal diseases largely underrecognized by scientists, governments, clinicians and pharmaceutical companies. The threat of fungal pathogens and antifungal resistance, even though it is a growing global issue, is being left out of the debate.”

Unlike bacteria, the close similarities between fungal and human cells which, say the experts, means it is hard to find treatments that selectively inhibit fungi with minimal toxicity to patients.

Back to square one

Professor Ferry Hagen added: “Despite the huge difficulties in developing them, several promising new agents including entirely new classes of molecules, have entered clinical trials in recent years. But even before they reach the market after years of development, fungicides with similar modes of action are developed by the agrochemical industry resulting in cross-resistance. That sets us back to square one again. It is true many essential crops are affected by fungi, so antifungal protection is required for food security. But the question is, at what price?”

The scientists recommend:

  • Worldwide agreement on restricting the use of certain classes of antifungal molecules for specific applications.
  • Collaboration on solutions and regulations that ensure food security and universal health for animals, plants, and humans.
  • Adding priority to AMR to fungal infections at the UN’s meeting in September.

Source: Universiteit van Amsterdam

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SARS-CoV-2 Shows no Signs of Resistance to Paxlovid – For Now

On By ModernMedia
SARS-CoV-2 infecting a human cell
Infected cell covered with SARS-CoV-2 viruses. Source: NIAID

Researchers monitoring SARS-CoV-2 for signs of resistance have found that Pfizer’s COVID drug Paxlovid is still effective against the coronavirus. Published in the journal Cell Research, [PDF] the study is one of the first to explore the full extent of mutations, but also provides evidence that mutations are moving in the direction of developing resistance to the drug.

Researchers concluded that Paxlovid’s mechanism of suppressing SARS-CoV-2 is still effective. The antiviral drug works by jamming the cell machinery of a key protein, known as the ‘main protease’ or Mpro, involved in replicating the virus. A number of antiviral drugs target viral proteases, such as those for HIV and hepatitis C.

With the global spread of Omicron, resulting in recent severe outbreaks in Asian countries which have previously pursued “zero COVID” strategies, the virus has been observed for signs of evolving treatment resistance. With only a few drugs that are available to treat COVID, physicians are counting on treatments like Paxlovid to stem the spread.

However, while the virus is currently not resistant, genetic analysis showed that the virus is starting to evolve in the direction of strains that could evade current treatments.

“There is hope, at least for now,” said study author Jun Wang, an associate professor at Rutgers University. “At this point, Omicron is still new enough so that treatments are still working. But as more people take Paxlovid, we will expect drug resistance to emerge.”

The scientists accessed a public database known as GISAID, studying the Mpro sequences of all strains of COVID detected so far. The protein is central to the reproduction of the virus and the target of the antiviral Paxlovid.

Comparing more recent strains with earlier strains around the world, the scientists searched for mutations in genetic sequences of Mpro that occur when a virus replicates. Mutations can lead to possible new structures of Mpro, which are generally correlated with drug resistance.

“We wanted to pick out if there is a mutation in the protease that’s a ‘red flag,’” A/Prof Wang said. “We did that because, generally speaking, as we have seen in the past, this would be the first sign of the development of resistance.”

The researchers found the top 25 most common new mutations in the main protease of many Omicron strains, a discovery A/Prof Wang characterised as “concerning,” with the most common one called P132H. When they tested Paxlovid against the Mpro with the P132H mutation, the antiviral was still effective. X-ray crystallography confirmed this by showing that the P132H did not change the Mpro structure significantly.

“Although this mutation does not cause drug resistance to Paxlovid, this implies that the virus can still evolve to create additional mutations that might cause drug resistance,” A/Prof Wang stated. “When a drug gets widespread use, it is just a matter of time before resistance appears.”

A/Prof’s Wang’s lab is working to develop new antivirals against COVID by targeting the Mpro and another key protein known as the papain-like protease. The best approach, he said, is to create a “cocktail” containing multiple antivirals to thwart resistance, as with HIV/AIDS and HCV.

Source: Rutgers University