Pharmacological and genetic activation of cAMP synthesis disrupts cholesterol utilization in Mycobacterium tuberculosis.
Pharmacological and genetic activation of cAMP synthesis disrupts cholesterol utilization in Mycobacterium tuberculosis.
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DOI：
10.1371/journal.ppat.1009862
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发表时间：
2022-03
期刊：
影响因子：
6.7
通讯作者：
VanderVen BC
中科院分区：
文献类型：
--
作者：
Wilburn KM;Montague CR;Qin B;Woods AK;Love MS;McNamara CW;Schultz PG;Southard TL;Huang L;Petrassi HM;VanderVen BC
越来越多的人认识到，细菌利用宿主来源的脂质，包括胆固醇，支持结核分枝杆菌（Mtb）的发病机制。这引起了人们对鉴定能够破坏体内结核分枝杆菌对胆固醇利用的新型抗生素的兴趣。在此，我们鉴定了Mtb腺苷酸环化酶Rv 1625 c的新型小分子激动剂（V-59），其刺激3 '，5'-环腺苷酸（cAMP）合成并抑制Mtb对胆固醇的利用。同样，使用互补的遗传方法，诱导细菌cAMP的合成独立的Rv 1625 c，我们证明，诱导cAMP的合成是足以抑制胆固醇利用结核分枝杆菌。虽然个别腺苷酸环化酶在结核分枝杆菌的生理作用在很大程度上是未知的，在这里，我们证明了Rv 1625 c的跨膜区是必需的胆固醇代谢过程中。最后，Rv 1625 c激动剂的药代动力学特性已经被优化，产生口服可利用的Rv 1625 c激动剂，其在感染的小鼠中损害Mtb发病机制。总的来说，这项工作证明了Rv 1625 c和cAMP信号传导在控制Mtb胆固醇代谢中的作用，并确定了cAMP信号传导可以被操纵以开发新的抗生素策略。结核分枝杆菌（Mtb）对常规抗生素的耐受性产生了鉴定新的药理学机制以抑制Mtb致病的需要。有越来越多的了解代谢适应结核分枝杆菌在感染过程中采取支持其生存和发病机制。这引起了人们对鉴定有效抑制这些体内代谢适应的小分子化合物的兴趣，同时克服了诸如不良的药代动力学性质或靶向途径中的冗余等挑战。Mtb胆固醇利用途径已被反复推测为理想的抗生素靶标，但缺乏成功抑制该复杂途径并适用于体内使用的化合物。在这里，我们建立了刺激cAMP合成Mtb是一种机制，足以阻止胆固醇利用的细菌，防止释放的关键代谢中间体，来自分解的胆固醇分子。这项工作还确定了Mtb腺苷酸环化酶Rv 1625 c的小分子激动剂，具有有前途的药理学特性，适合在体内研究期间使用。这些Rv 1625 c激动剂增加cAMP合成，抑制Mtb对胆固醇的利用，并破坏慢性感染小鼠模型中的Mtb发病机制。
There is a growing appreciation for the idea that bacterial utilization of host-derived lipids, including cholesterol, supports Mycobacterium tuberculosis (Mtb) pathogenesis. This has generated interest in identifying novel antibiotics that can disrupt cholesterol utilization by Mtb in vivo. Here we identify a novel small molecule agonist (V-59) of the Mtb adenylyl cyclase Rv1625c, which stimulates 3’, 5’-cyclic adenosine monophosphate (cAMP) synthesis and inhibits cholesterol utilization by Mtb. Similarly, using a complementary genetic approach that induces bacterial cAMP synthesis independent of Rv1625c, we demonstrate that inducing cAMP synthesis is sufficient to inhibit cholesterol utilization in Mtb. Although the physiological roles of individual adenylyl cyclase enzymes in Mtb are largely unknown, here we demonstrate that the transmembrane region of Rv1625c is required during cholesterol metabolism. Finally, the pharmacokinetic properties of Rv1625c agonists have been optimized, producing an orally-available Rv1625c agonist that impairs Mtb pathogenesis in infected mice. Collectively, this work demonstrates a role for Rv1625c and cAMP signaling in controlling cholesterol metabolism in Mtb and establishes that cAMP signaling can be pharmacologically manipulated for the development of new antibiotic strategies. The recalcitrance of Mycobacterium tuberculosis (Mtb) to conventional antibiotics has created a need to identify novel pharmacological mechanisms to inhibit Mtb pathogenesis. There is a growing understanding of the metabolic adaptations Mtb adopts during infection to support its survival and pathogenesis. This has generated interest in identifying small molecule compounds that effectively inhibit these in vivo metabolic adaptations, while overcoming challenges like poor pharmacokinetic properties or redundancy in target pathways. The Mtb cholesterol utilization pathway has repeatedly been speculated to be a desirable antibiotic target, but compounds that successfully inhibit this complex pathway and are suitable for use in vivo are lacking. Here, we establish that stimulating cAMP synthesis in Mtb is a mechanism that is sufficient to block cholesterol utilization by the bacterium, preventing the release of key metabolic intermediates that are derived from breakdown of the cholesterol molecule. This work also identifies small molecule agonists of the Mtb adenylyl cyclase Rv1625c that have promising pharmacological properties and are suitable for use during in vivo studies. These Rv1625c agonists increase cAMP synthesis, inhibit cholesterol utilization by Mtb, and disrupt Mtb pathogenesis in mouse models of chronic infection.
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3.6
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影响因子：
4.6
作者：
Aiewsakun P;Prombutara P;Siregar TAP;Laopanupong T;Kanjanasirirat P;Khumpanied T;Borwornpinyo S;Tong-Ngam P;Tubsuwan A;Srilohasin P;Chaiprasert A;Ruangchai W;Palittapongarnpim P;Prammananan T;VanderVen BC;Ponpuak M
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