Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA; email:
Annu Rev Microbiol. 2022 Sep 8;76:281-304. doi: 10.1146/annurev-micro-041320-110408. Epub 2022 Jun 1.
Antibiotic resistance is a serious public health concern, and new drugs are needed to ensure effective treatment of many bacterial infections. Bacterial type II fatty acid synthesis (FASII) is a vital aspect of bacterial physiology, not only for the formation of membranes but also to produce intermediates used in vitamin production. Nature has evolved a repertoire of antibiotics inhibiting different aspects of FASII, validating these enzymes as potential targets for new antibiotic discovery and development. However, significant obstacles have been encountered in the development of FASII antibiotics, and few FASII drugs have advanced beyond the discovery stage. Most bacteria are capable of assimilating exogenous fatty acids. In some cases they can dispense with FASII if fatty acids are present in the environment, making the prospects for identifying broad-spectrum drugs against FASII targets unlikely. Single-target, pathogen-specific FASII drugs appear the best option, but a major drawback to this approach is the rapid acquisition of resistance via target missense mutations. This complication can be mitigated during drug development by optimizing the compound design to reduce the potential impact of on-target missense mutations at an early stage in antibiotic discovery. The lessons learned from the difficulties in FASII drug discovery that have come to light over the last decade suggest that a refocused approach to designing FASII inhibitors has the potential to add to our arsenal of weapons to combat resistance to existing antibiotics.
抗生素耐药性是一个严重的公共卫生问题，需要新的药物来确保有效治疗许多细菌感染。细菌 II 型脂肪酸合成（FASII）是细菌生理学的一个重要方面，不仅对于膜的形成很重要，而且对于产生用于维生素生产的中间体也很重要。自然界已经进化出了一系列抑制 FASII 不同方面的抗生素，这些酶作为新抗生素发现和开发的潜在靶点得到了验证。然而，在开发 FASII 抗生素方面遇到了重大障碍，很少有 FASII 药物能够超越发现阶段。大多数细菌能够同化外源性脂肪酸。在某些情况下，如果环境中存在脂肪酸，它们可以不使用 FASII，这使得识别针对 FASII 靶标的广谱药物的前景不太可能。针对单一靶点、病原体特异性的 FASII 药物似乎是最佳选择，但这种方法的一个主要缺点是，通过靶标错义突变迅速获得耐药性。在药物开发过程中，可以通过优化化合物设计来减轻这种复杂性，从而减少抗生素发现早期靶标错义突变的潜在影响。过去十年中，在 FASII 药物发现方面遇到的困难所带来的教训表明，重新集中精力设计 FASII 抑制剂有可能为我们对抗现有抗生素耐药性的武器库增添新的武器。
