Elucidating the inhibition of peptidoglycan biosynthesis in Staphylococcus aureus by albocycline, a macrolactone isolated from Streptomyces maizeus.
Elucidating the inhibition of peptidoglycan biosynthesis in Staphylococcus aureus by albocycline, a macrolactone isolated from Streptomyces maizeus.
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DOI：
10.1016/j.bmc.2018.05.017
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发表时间：
2018-07-23
影响因子：
3.5
通讯作者：
Andrade RB
中科院分区：
文献类型：
--
作者：
Liang H;Zhou G;Ge Y;D'Ambrosio EA;Eidem TM;Blanchard C;Shehatou C;Chatare VK;Dunman PM;Valentine AM;Voelz VA;Grimes CL;Andrade RB
抗生素耐药性是对全球公共卫生的严重威胁，耐甲氧西林金黄色葡萄球菌（MRSA）就是一个尖锐的例子。大环内酯的天然产物白环素是近年来发现的一种有前途的抗生素候选物，可用于治疗耐甲氧西林金黄色葡萄球菌（MRSA）和万古霉素耐药的链球菌。金黄色葡萄球菌（VRSA），其是另一种临床相关的抗生素抗性菌株。此外，假设白环素的抗微生物活性来源于肽聚糖的抑制（即，细菌细胞壁）生物合成。在此，进行初步的机制研究，以测试的假设，即albocycline抑制MurA，酶催化肽聚糖生物合成的第一步，使用生物测定以及分子建模和模拟研究的组合。计算模型表明，albocycline存在于溶液中的两种构象，这些构象的模拟受体结构的合奏正确预测的优先结合S的计算对接。金黄色葡萄球菌MurA-催化肽聚糖生物合成的第一步的酶-在大肠杆菌（E. coli）MurA.从产生菌（Streptomyces maizeus）中分离的白霉素对S. aureus MurA（IC_（50）为480 μM），但不抑制E. coli MurA.白霉素对耐药链球菌的抗菌活性。金黄色葡萄球菌上级万古霉素，优先抑制革兰氏阳性菌。MTT法检测表明，Albocycline对人HepG 2细胞无毒性。虽然这些研究表明，白霉素是一个有前途的领导候选人对耐药的S。金黄色葡萄球菌，他们一起表明，MurA不是主要目标，进一步的工作是必要的，以确定主要的生物靶标。
Antibiotic resistance is a serious threat to global public health, and methicillin-resistant Staphylococcus aureus (MRSA) is a poignant example. The macrolactone natural product albocycline, derived from various Streptomyces strains, was recently identified as a promising antibiotic candidate for the treatment of both MRSA and vancomycin-resistant S. aureus (VRSA), which is another clinically relevant and antibiotic resistant strain. Moreover, it was hypothesized that albocycline’s antimicrobial activity was derived from the inhibition of peptidoglycan (i.e., bacterial cell wall) biosynthesis. Herein, preliminary mechanistic studies are performed to test the hypothesis that albocycline inhibits MurA, the enzyme that catalyzes the first step of peptidoglycan biosynthesis, using a combination of biological assays alongside molecular modeling and simulation studies. Computational modeling suggests albocycline exists as two conformations in solution, and computational docking of these conformations to an ensemble of simulated receptor structures correctly predicted preferential binding to S. aureus MurA—the enzyme that catalyzes the first step of peptidoglycan biosynthesis— over Escherichia coli (E. coli) MurA. Albocycline isolated from the producing organism (Streptomyces maizeus) weakly inhibited S. aureus MurA (IC50 of 480 μM) but did not inhibit E. coli MurA. The antimicrobial activity of albocycline against resistant S. aureus strains was superior to that of vancomycin, preferentially inhibiting Gram-positive organisms. Albocycline was not toxic to human HepG2 cells in MTT assays. While these studies demonstrate that albocycline is a promising lead candidate against resistant S. aureus, taken together they suggest that MurA is not the primary target, and further work is necessary to identify the major biological target.
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影响因子：
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作者：
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通讯作者：
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