Garcia-Rubio Rocio, Gonzalez-Jimenez Irene, Lucio Jose, Mellado Emilia
Mycology Reference Laboratory, National Centre for Microbiology, Instituto de Salud Carlos III (ISCIII), Majadahonda, Madrid, 28222, Spain.
Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, 07012, USA.
Appl Environ Microbiol. 2021 Mar 1;87(5). doi: 10.1128/AEM.02539-20. Epub 2020 Dec 18.
Drug resistance poses a serious threat to human health and agricultural production. Azole drugs are the largest group of 14-α sterol demethylation inhibitor fungicides that are used both in agriculture and in clinical practice. As plant pathogenic molds share their natural environment with fungi that cause opportunistic infections in humans, both are exposed to a strong and persistent pressure of demethylase inhibitor (DMI) fungicides, including imidazole and triazole drugs. As a result, a loss of efficacy has occurred for this drug class in several species. In the clinical setting, azole resistance is a growing public health problem and finding the source of this resistance has gained much attention. It is urgent to determine if there is a direct link between the agricultural use of azole compounds and the different resistance mechanisms described for clinical triazoles. In this work we have performed susceptibility testing to clinical triazoles and crop protection DMIs using a collection of azole susceptible and resistant strains which harbor most of the described azole resistance mechanisms. Various DMI susceptibility profiles have been found in the different populations groups based on their azole resistance mechanism and previous WGS analysis, which suggests that the different resistance mechanisms have different origins and are specifically associated to the local use of a particular DMI. Due to the worldwide emergence of azole resistance, this opportunistic pathogen poses a serious health threat and, therefore, it has been included in the Watch List of the CDC 2019 Antimicrobial Resistance Threats Report. Azoles play a critical role in the control and management of fungal diseases, not only in the clinical setting but also in agriculture. Thus, azole resistance leads to a limited therapeutic arsenal which reduces the treatment options for aspergillosis patients, increasing their mortality risk. Evidence is needed to understand whether azole resistance is emerging from an agricultural source due to the extended use of demethylase inhibitors as fungicides, or whether it is coming from somewhere else such as the clinical setting. If the environmental route is demonstrated, the current use and management of azole antifungal compounds might be forced to change in the forthcoming years.
耐药性对人类健康和农业生产构成严重威胁。唑类药物是最大的一类14-α甾醇去甲基化抑制剂杀菌剂，在农业和临床实践中均有使用。由于植物致病霉菌与可导致人类机会性感染的真菌共享自然环境，二者都面临着包括咪唑和三唑类药物在内的去甲基化酶抑制剂（DMI）杀菌剂的强大而持续的压力。因此，这类药物在多个物种中已出现疗效丧失的情况。在临床环境中，唑类耐药性是一个日益严重的公共卫生问题，找出这种耐药性的来源已备受关注。迫切需要确定唑类化合物在农业中的使用与临床三唑类药物所描述的不同耐药机制之间是否存在直接联系。在这项工作中，我们使用了一组对唑类敏感和耐药的菌株进行了临床三唑类药物和作物保护DMI的药敏试验，这些菌株具有大多数已描述的唑类耐药机制。基于它们的唑类耐药机制和先前的全基因组测序分析，在不同种群组中发现了各种DMI药敏谱，这表明不同的耐药机制有不同的起源，并且与特定DMI的局部使用有特定关联。由于唑类耐药性在全球范围内出现，这种机会性病原体对健康构成严重威胁，因此，它已被列入美国疾病控制与预防中心（CDC）2019年抗菌药物耐药性威胁报告的观察名单。唑类不仅在临床环境中，而且在农业中，在真菌疾病的控制和管理中都起着关键作用。因此，唑类耐药性导致治疗手段有限，并减少了曲霉病患者的治疗选择，增加了他们的死亡风险。需要证据来了解唑类耐药性是由于作为杀菌剂的去甲基化酶抑制剂的广泛使用而从农业来源出现，还是来自其他地方，如临床环境。如果环境途径得到证实，唑类抗真菌化合物的当前使用和管理可能在未来几年被迫改变。
