Carney Daniel W, Compton Corey L, Schmitz Karl R, Stevens Julia P, Sauer Robert T, Sello Jason K
Department of Chemistry, Brown University, 324 Brook Street, Providence, RI 02912 (USA).
Chembiochem. 2014 Oct 13;15(15):2216-20. doi: 10.1002/cbic.201402358. Epub 2014 Sep 11.
The development of new antibacterial agents, particularly those with unique biological targets, is essential to keep pace with the inevitable emergence of drug resistance in pathogenic bacteria. We identified the minimal structural component of the cyclic acyldepsipeptide (ADEP) antibiotics that exhibits antibacterial activity. We found that N-acyldifluorophenylalanine fragments function via the same mechanism of action as ADEPs, as evidenced by the requirement of ClpP for the fragments' antibacterial activity, the ability of fragments to activate Bacillus subtilis ClpP in vitro, and the capacity of an N-acyldifluorophenylalanine affinity matrix to capture ClpP from B. subtilis cell lysates. N-acyldifluorophenylalanine fragments are much simpler in structure than the full ADEPs and are also highly amenable to structural diversification. Thus, the stage has been set for the development of non-peptide activators of ClpP that can be used as antibacterial agents.
开发新型抗菌剂，尤其是那些具有独特生物学靶点的抗菌剂，对于跟上病原菌中耐药性不可避免的出现至关重要。我们确定了具有抗菌活性的环脂肽（ADEP）抗生素的最小结构成分。我们发现N-酰基二氟苯丙氨酸片段的作用机制与ADEP相同，这一点得到了以下证据的支持：片段的抗菌活性需要ClpP，片段在体外激活枯草芽孢杆菌ClpP的能力，以及N-酰基二氟苯丙氨酸亲和基质从枯草芽孢杆菌细胞裂解物中捕获ClpP的能力。N-酰基二氟苯丙氨酸片段的结构比完整的ADEP简单得多，并且也非常适合进行结构多样化。因此，已经为开发可作为抗菌剂的ClpP非肽激活剂奠定了基础。
