L-Arginine is the precursor of nitric oxide (NO), a host immune effector against intracellular pathogens including Mycobacterium tuberculosis (M. tb). Pathogens including M. tb have evolved various strategies targeting arginine to block the production of NO for better survival and proliferation. However, L-arginine metabolism and regulation in Mycobacterium are poorly understood. Here, we report the identification of M. smegmatis MSMEG_1415 (homolog of M. tb Rv2324) as an arginine-responsive transcriptional factor regulating the arginase pathway. In the absence of L-arginine, MSMEG_1415 acts as a repressor to inhibit the transcription of the roc (for arginine, ornithine catabolism) gene cluster, thereby switching off the arginase pathway. Treatment with L-arginine relieves the transcriptional inhibition of MSMEG_1415 on the roc gene cluster to activate the arginase pathway. Moreover, the L-arginine-MSMEG_1415 complex activates the transcription of the roc gene cluster by recognizing and binding a 15-bp palindrome motif, thereby preventing the excess accumulation of L-arginine in M. smegmatis. Physiologically, MSMEG_1415 confers mycobacteria resistance to starvation and fluoroquinolones exposure, suggestive of its important role in M. smegmatis persistence. The results uncover a unique regulatory mechanism of arginine metabolism in mycobacteria and identify M. tb Rv2324 as an attractive candidate target for the design of drugs against tuberculosis.

L-精氨酸是一氧化氮 (NO) 的前体，一氧化氮是针对包括结核分枝杆菌( M. tb ) 在内的细胞内病原体的宿主免疫效应物。包括结核分枝杆菌在内的病原体已经进化出各种针对精氨酸的策略，以阻止 NO 的产生，从而更好地生存和增殖。然而，人们对分枝杆菌中的L-精氨酸代谢和调节知之甚少。在这里，我们报告了耻垢分枝杆菌MSMEG_1415（结核分枝杆菌 Rv2324 的同源物）作为调节精氨酸酶途径的精氨酸反应性转录因子的鉴定。在没有 L-精氨酸的情况下，MSMEG_1415 充当阻遏物来抑制roc的转录（对于精氨酸，鸟氨酸分解代谢）基因簇，从而关闭精氨酸酶途径。L-精氨酸处理可减轻 MSMEG_1415 对roc基因簇的转录抑制，从而激活精氨酸酶途径。此外，L-精氨酸-MSMEG_1415 复合物通过识别和结合 15 bp 回文基序激活roc基因簇的转录，从而防止 L-精氨酸在耻垢分枝杆菌中的过量积累。在生理学上，MSMEG_1415 赋予分枝杆菌对饥饿和氟喹诺酮类药物暴露的抵抗力，这表明它在耻垢分枝杆菌持续存在中的重要作用。结果揭示了分枝杆菌中精氨酸代谢的独特调控机制，并鉴定了M. tb Rv2324 作为设计抗结核药物的有吸引力的候选靶标。