Juanjuan Ding,Wenyan Ba,Shengping You,Wei Qi,Rongxin Su
γ-aminobutyric acid (GABA) is an important inhibitory neurotransmitter in the brain with many physiological functions. Therefore, this work establishes an efficient biosynthesis process to achieve the high production of food-grade GABA. Firstly, we adopted a directional colorimetric screening method and then obtained the strain Lactobacillus brevis ( Lb. brevis) CGMCC 24975 with 22.61 g/L GABA in shake flasks, much higher than Lb. brevis ATCC 367 (3.07 g/L) due to its more efficient and stable expression of its glutamate decarboxylase (GAD) system. After exploring the effects of optimal fermentation conditions and oxygen on GABA production, we found that anaerobic fermentation could increase GABA production by up-regulating gad operon expression and activating GADase. Finally, we developed an oil-sealed anaerobic fermentation process with 157.90 g/L GABA in a 5 L bioreactor, which was 6.98-fold of that in shake flasks. This work includes a complete process from screening GABA-producing strains to developing efficient fermentation processes, laying the foundation for producing food-safe GABA.
Liu Yuan,Tong Ziwen,Shi Jingru,Jia Yuqian,Deng Tian,Wang Zhiqiang
Antimicrobial resistance has been a growing concern that gradually undermines our tradition treatment regimens. The fact that few antibacterial drugs with new scaffolds or targets have been approved in the past two decades aggravates this crisis. Repurposing drugs as potent antibiotic adjuvants offers a cost-effective strategy to mitigate the development of resistance and tackle the increasing infections by multidrug-resistant (MDR) bacteria. Herein, we found that benzydamine, a widely used non‐steroidal anti‐inflammatory drug in clinic, remarkably potentiated broad-spectrum antibiotic-tetracyclines activity against a panel of clinically important pathogens, including MRSA, VRE, MCRPEC and tet (X)-positive Gram-negative bacteria. Mechanistic studies showed that benzydamine dissipated membrane potential ( ▵ Ψ) in both Gram-positive and Gram-negative bacteria, which in turn upregulated the transmembrane proton gradient ( ▵ pH) and promoted the uptake of tetracyclines. Additionally, benzydamine exacerbated the oxidative stress by triggering the production of ROS and suppressing GAD system-mediated oxidative defensive. This mode of action explains the great bactericidal activity of the doxycycline-benzydamine combination against different metabolic states of bacteria involve persister cells. As a proof-of-concept, the in vivo efficacy of this drug combination was evidenced in multiple animal infection models. These findings indicate that benzydamine is a potential tetracyclines adjuvant to address life-threatening infections by MDR bacteria.
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