Emergence of antibiotic-resistant bacteria constitutes an increasing threat to human health. For example, treatment options for Staphylococcus aureus infections is declining with the worldwide spreading of highly virulent community-associated methicillin-resistant S. aureus (CA-MRSA) strains. Anti-virulence therapy has been proposed as an alternative treatment strategy, as it typically involves inhibition of expression of virulence factors rather than direct bacterial killing, thereby attenuating the risk of resistance development. An intriguing target is the agr quorum-sensing system, which is a major inducer of virulence in CA-MRSA upon activation by agr-encoded staphylococcal autoinducing peptides (AIPs).

In the present work a previously identified lactam hybrid analogue based on the marine depsipeptide solonamide B and the general structure of AIPs was investigated with respect to structure–function relationships. An array of 27 analogues exploring expansion of ring size, type of side chain, amino acid substitutions, and stereochemistry was designed and tested for AgrC-inhibitory activity. Interestingly, it was found that an analogue derived from the mirror image of the original hit proved to be the hitherto most efficient AgrC inhibitor resembling solonamide B in amino acid sequence. This and closely related compounds were 20- to 40-fold more potent in AgrC inhibition than the starting hit compound.

抗生素抗性细菌的出现对人类健康构成了越来越大的威胁。例如，随着高毒力社区相关性耐甲氧西林金黄色葡萄球菌（CA-MRSA）菌株在世界范围内的传播，金黄色葡萄球菌感染的治疗选择正在减少。已经提出了抗毒力疗法作为替代治疗策略，因为它通常涉及抑制毒力因子的表达而不是直接杀死细菌，从而降低了耐药性发展的风险。一个引人入胜的目标是农业群体感应系统，它是通过农业编码的葡萄球菌自动诱导肽（AIP）激活后，CA-MRSA中毒力的主要诱因。

在目前的工作中，研究人员基于结构-功能关系研究了先前鉴定的基于海洋二肽肽soloamide B和AIPs的一般结构的内酰胺杂合体。设计并测试了27种类似物，探讨了环大小的扩大，侧链类型，氨基酸取代和立体化学的阵列，并测试了其对AgrC的抑制活性。有趣的是，发现源自原始命中的镜像的类似物被证明是迄今为止最有效的类似于氨基酸序列上的磺酰胺B的AgrC抑制剂。该化合物和密切相关的化合物对AgrC的抑制作用比起始命中化合物高20至40倍。