Department of Chemistry, American University, Washington, DC 20016, USA.
Tuberculosis Research Section, LCIM, NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Bioorg Med Chem. 2019 Oct 15;27(20):115050. doi: 10.1016/j.bmc.2019.115050. Epub 2019 Aug 20.
C4-phenylthio β-lactams are a new family of antibacterial agents that have activity against two phylogenetically distant bacteria - Mycobacterium tuberculosis (Mtb) and Moraxella catarrhalis (M. cat). These compounds are effective against β-lactamase producing Mtb and M. cat unlike the clinically relevant β-lactam antibiotics. The structure-activity relationship for the C4 phenylthio β-lactams has not yet been completely defined. Earlier efforts in our laboratories established that the C4-phenylthio substituent is essential for antimicrobial activity, while the N1 carbamyl substituent plays a more subtle role. In this present study, we investigated the role that the stereochemistry at C4 plays in these compounds' antibacterial activity. This was achieved by synthesizing and testing the antimicrobial activity of diastereomers with a chiral carbamyl group at N1. Our findings indicate that a strict stereochemistry for the C4-phenylthio β-lactams is not required to obtain optimal anti-Mtb and anti-M. cat activity. Furthermore, the structure-bioactivity profiles more closely relate to the electronic requirement of the phenylthiogroup. In addition, the MICs of Mtb are sensitive to growth medium composition. Select compounds showed activity against non-replicating and multi-drug resistant Mtb.
C4-苯硫基β-内酰胺是一类新型的抗菌药物，对两种系统发育上相距较远的细菌——结核分枝杆菌（Mtb）和卡他莫拉菌（M. cat）具有活性。与临床相关的β-内酰胺抗生素不同，这些化合物对产β-内酰胺酶的 Mtb 和 M. cat 有效。C4-苯硫基β-内酰胺的构效关系尚未完全确定。我们实验室的早期研究表明，C4-苯硫基取代基对于抗菌活性是必需的，而 N1 氨甲酰基取代基则起着更为微妙的作用。在本研究中，我们研究了 C4 立体化学在这些化合物的抗菌活性中所起的作用。这是通过合成和测试具有手性氨甲酰基取代基的非对映异构体的抗菌活性来实现的。我们的发现表明，C4-苯硫基β-内酰胺不需要严格的立体化学就可以获得最佳的抗 Mtb 和抗 M. cat 活性。此外，结构-生物活性谱更密切地与苯硫基团的电子需求相关。此外，Mtb 的 MIC 对生长培养基的组成敏感。一些选择的化合物对非复制和耐多药的 Mtb 具有活性。
