Alfei Silvana
Department of Pharmacy, University of Genoa, Viale Cembrano, 4, 16148 Genova, Italy.
Pharmaceutics. 2024 Jan 5;16(1):80. doi: 10.3390/pharmaceutics16010080.
Since they are difficult and sometimes impossible to treat, infections sustained by multidrug-resistant (MDR) pathogens, emerging especially in nosocomial environments, are an increasing global public health concern, translating into high mortality and healthcare costs. In addition to having acquired intrinsic abilities to resist available antibiotic treatments, MDR bacteria can transmit genetic material encoding for resistance to non-mutated bacteria, thus strongly decreasing the number of available effective antibiotics. Moreover, several pathogens develop resistance by forming biofilms (BFs), a safe and antibiotic-resistant home for microorganisms. BFs are made of well-organized bacterial communities, encased and protected in a self-produced extracellular polymeric matrix, which impedes antibiotics' ability to reach bacteria, thus causing them to lose efficacy. By adhering to living or abiotic surfaces in healthcare settings, especially in intensive care units where immunocompromised older patients with several comorbidities are hospitalized BFs cause the onset of difficult-to-eradicate infections. In this context, recent studies have demonstrated that quaternary ammonium compounds (QACs), acting as membrane disruptors and initially with a low tendency to develop resistance, have demonstrated anti-BF potentialities. However, a paucity of innovation in this space has driven the emergence of QAC resistance. More recently, quaternary phosphonium salts (QPSs), including tri-phenyl alkyl phosphonium derivatives, achievable by easy one-step reactions and well known as intermediates of the Wittig reaction, have shown promising anti-BF effects in vitro. Here, after an overview of pathogen resistance, BFs, and QACs, we have reviewed the QPSs developed and assayed to this end, so far. Finally, the synthetic strategies used to prepare QPSs have also been provided and discussed to spur the synthesis of novel compounds of this class. We think that the extension of the knowledge about these materials by this review could be a successful approach to finding effective weapons for treating chronic infections and device-associated diseases sustained by BF-producing MDR bacteria.
由于由多重耐药（MDR）病原体引起的感染难以治疗，有时甚至无法治疗，特别是在医院环境中不断出现，这已成为日益严重的全球公共卫生问题，导致高死亡率和医疗成本。除了具有抵抗现有抗生素治疗的内在能力外，MDR细菌还可以将编码耐药性的遗传物质传递给未发生突变的细菌，从而大大减少了可用有效抗生素的数量。此外，几种病原体通过形成生物膜（BFs）产生耐药性，生物膜是微生物安全且抗抗生素的家园。BFs由组织良好的细菌群落组成，包裹在自身产生的细胞外聚合物基质中并受到保护，这阻碍了抗生素接触细菌的能力，从而使其失去效力。通过粘附在医疗环境中的生物或非生物表面上，特别是在患有多种合并症的免疫功能低下的老年患者住院的重症监护病房中，BFs会引发难以根除的感染。在这种背景下，最近的研究表明，季铵化合物（QACs）作为膜破坏剂，最初产生耐药性的倾向较低，已显示出抗BF的潜力。然而，该领域缺乏创新导致了QAC耐药性的出现。最近，季鏻盐（QPSs），包括三苯基烷基鏻衍生物，可通过简单的一步反应获得，并且作为维蒂希反应的中间体而广为人知，已在体外显示出有前景的抗BF效果。在此，在概述病原体耐药性、BFs和QACs之后，我们回顾了迄今为止为此目的开发和检测的QPSs。最后，还提供并讨论了用于制备QPSs的合成策略，以促进此类新型化合物的合成。我们认为，通过本综述扩展对这些材料的认识可能是找到有效武器来治疗由产生BF的MDR细菌引起的慢性感染和与设备相关疾病的成功方法。
