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<p>The emergence of azole-resistant <i>Candida</i> infections is a major concern. A key mechanism is the gain of resistance through amino acid substitutions in the sterol 14α-demethylase, the main target of azole drugs. While numerous resistant substitutions are known, the pattern of such substitutions remains unclear. We hypothesized that resistant substitutions occur disproportionately at azole-binding sites. We compiled 2222 instances of azole-resistant substitutions from the literature and performed extensive computational sequence analyses. Altogether, there were 169 known substitutions at 133 sites in sterol 14α-demethylases of seven <i>Candida</i> species, whereas <i>C. albicans</i> alone had 120 substitutions at 97 sites. Just 10 sites and 18 substitutions (such as Y132F/H, K143R, D116E, and G464S) accounted for 75% of the total instances. Only about 48% of the sites were present within previously recognized hotspot regions, while just 33% of the azole-interacting residues had known resistant substitutions, most of them with only a few instances. The literature data on azole-resistant substitutions in <i>Candida</i> appear to be highly biased, as a few substitutions, such as Y132F/H and K143R, were preferentially sought and reported with over 1,000 instances. Additionally, there were numerous reports of “resistant” substitutions in azole-susceptible <i>Candida</i> isolates. Our study provides new perspectives into azole resistance.</p>

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Azole resistance: patterns of amino acid substitutions in Candida sterol 14α-demethylase

  • 期刊论文

  • 发表日期：

    2025年4月17日

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  • R. Shyama Prasad Rao,
  • Larina Pinto,
  • Rajesh P. Shastry,
  • Tikam Chand Dakal,
  • Prashanth Suravajhala,
  • V. K. Sashindran,
  • Sudeep D. Ghate

摘要

The emergence of azole-resistant Candida infections is a major concern. A key mechanism is the gain of resistance through amino acid substitutions in the sterol 14α-demethylase, the main target of azole drugs. While numerous resistant substitutions are known, the pattern of such substitutions remains unclear. We hypothesized that resistant substitutions occur disproportionately at azole-binding sites. We compiled 2222 instances of azole-resistant substitutions from the literature and performed extensive computational sequence analyses. Altogether, there were 169 known substitutions at 133 sites in sterol 14α-demethylases of seven Candida species, whereas C. albicans alone had 120 substitutions at 97 sites. Just 10 sites and 18 substitutions (such as Y132F/H, K143R, D116E, and G464S) accounted for 75% of the total instances. Only about 48% of the sites were present within previously recognized hotspot regions, while just 33% of the azole-interacting residues had known resistant substitutions, most of them with only a few instances. The literature data on azole-resistant substitutions in Candida appear to be highly biased, as a few substitutions, such as Y132F/H and K143R, were preferentially sought and reported with over 1,000 instances. Additionally, there were numerous reports of “resistant” substitutions in azole-susceptible Candida isolates. Our study provides new perspectives into azole resistance.