探討金黃色葡萄球菌鐵載體Staphyloferrin A結構對於螯合鐵能力與細菌攝取的關係

Abstract

耐甲氧西林金黃色葡萄球菌（MRSA）是β-內酰胺抗性金黃色葡萄球菌菌株，它在世界範圍內傳播並導致30％的死亡率。在宿主體內，金黃色葡萄球菌分泌鐵載體Staphyloferrin A（簡稱SA）以獲得三價鐵離子，這對其生長至關重要。因此，SA可能可以被用來作為針對金黃色葡萄球菌有專一性的辨識單元，設計一個鐵載體-抗生素共軛化合物，使抗生素能藉由SA的辨識通道而進入細菌體內，這種策略稱為[特洛伊木馬]。而了解SA如何被金黃色葡萄球菌吸收，能夠使我們更好的設計出新的鐵載體-抗生素共軛化合物。 在這裡，我們合成了幾種SA類似物來研究結構和細菌攝取之間的關係。我們藉由操縱鳥氨酸的手性、骨架大小和羧基以及檸檬酸手性，來探究SA結構對其細菌攝取效率的影響。 從研究中，我們發現SA手性的改變對鐵螯合能力幾乎沒有影響。我們合成出的螢光素-SA共軛物能夠標記金黃色葡萄球菌，但我們也發現，如果是用L-鳥氨酸作為骨架的SA類似物，標記金黃色葡萄球菌的效率就會差很多，因此我們認為維持D-鳥氨酸的手性對於標記金黃色葡萄球菌是很重要的。若要設計鐵載體-抗生素共軛物，就必須維持鳥氨酸的手性。

Methicillin-Resistant Staphylococcus aureus (MRSA) is β-lactam resistant S. aureus strain which spreads worldwide and causes 30% fatality death. Inside host, secreting Staphyloferrin A (SA) by S. aureus to acquire Fe(III) is vital to its growth. Hence, SA might be utilized as a strain-specific warhead against S. aureus in Trojan-horse antibiotic. Understanding how SA is taken up by S. aureus enable us to design novel siderophore-antimicrobial conjugates. Here, we synthesized several analogs of SA to investigate the relationship between structure and bacterial uptake. We investigate how SA structure affect its bacterial uptake efficiency through manipulating the chirality, backbone size, and carboxyl group of ornithine, as well as citric acid chirality. Analogs with diverse chiral centers have little impact on iron chelation ability. With fluorescent SA analogs, we found that the change in chirality in ornithine backbone significantly decreased bacterial targeting, suggesting maintaining this chirality is necessary in molecular design of siderophore-antimicrobial conjugates.