Morán-Díaz Jessica R, Neveros-Juárez Francisco, Arellano-Mendoza Mónica Griselda, Quintana-Zavala Delia, Lara-Salazar Omar, Trujillo-Ferrara José Guadalupe, Guevara-Salazar J Alberto
Organic Chemistry Laboratory. Centro de Investigación en Ciencia Aplicada y Tecnología Avanzada, Unidad Legaria, Instituto Politécnico Nacional, Legaria No. 694, C.P. 11500, Mexico City, Mexico.
Department of Pharmacology, Biochemistry and Section of Postgraduate Studies and Research. Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, S/N, Col. Santo Tomás, Alcaldía Miguel Hidalgo, C.P. 11340, Mexico City, Mexico.
Mol Divers. 2024 Oct;28(5):3027-3043. doi: 10.1007/s11030-023-10730-7. Epub 2023 Sep 21.
Solving the worldwide problem of growing bacterial drug resistance will require a short-run and medium-term strategy. Structure-activity relationship (SAR) and quantitative SAR (QSAR) analyses have recently been utilized to reveal the molecular basis of the antibacterial activity and antibacterial spectrum of penicillins, the use of which is no longer solely empirical. Likewise, a more rational drug design can be achieved with cephalosporins, the largest group of β-lactam antibiotics. The current contribution aimed to establish the molecular and physicochemical basis of the antibacterial activity of five generations of cephalosporins on methicillin-sensitive (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA). With SAR and QSAR analyses, the molecular portions that provide essential and additional antibacterial activity were identified. The substitutions with greater volume and polarity on the R side chain of the cephem nucleus increase potency on MSSA. The best effect is produced by substitutions with polar nitrogen atoms at the alpha-carbon (Cα). Substitutions with greater volume and polarity on the R side chain further enhance antibacterial activity. In contrast, the effect against MRSA seems to be independent of any substitution on R or at the Cα, while depending on the accessory portions with greater volume and polarity on R.
解决全球范围内日益严重的细菌耐药性问题需要短期和中期战略。结构-活性关系（SAR）和定量结构-活性关系（QSAR）分析最近已被用于揭示青霉素抗菌活性和抗菌谱的分子基础，青霉素的使用不再仅仅是经验性的。同样，对于最大的β-内酰胺抗生素类头孢菌素，可以实现更合理的药物设计。当前的研究旨在确定五代头孢菌素对甲氧西林敏感金黄色葡萄球菌（MSSA）和耐甲氧西林金黄色葡萄球菌（MRSA）抗菌活性的分子和物理化学基础。通过SAR和QSAR分析，确定了提供基本和额外抗菌活性的分子部分。头孢烯核R侧链上体积和极性更大的取代基增加了对MSSA的效力。最佳效果是由α-碳（Cα）上带有极性氮原子的取代基产生的。R侧链上体积和极性更大的取代基进一步增强抗菌活性。相比之下，对MRSA的作用似乎与R或Cα上的任何取代无关，而取决于R上体积和极性更大的附属部分。
