Killing bacteria from within: In search of novel antibiotic targets

正如SARS-CoV-2病毒大流行所强调的那样，传染病对人类生命构成的威胁不可低估。在全球每年5600万例死亡中，18%是由传染病造成的。死亡率并不是唯一的负担;联合国估计SARS-CoV-2大流行的成本将达到1万亿美元。继发性细菌感染在病毒大流行期间具有显著的影响，如已经观察到的第一个HIV和现在的SARS-CoV-2。由细菌_结核分枝杆菌_（Mtb）引起的结核病是世界上最致命的传染病，每年导致1000万例病例和160万例死亡。病原体是传染病的病原微生物，它们对药物的抗药性令人严重关切。预计到2050年，耐药结核病将给世界造成16.7万亿美元的损失。发现治疗传染病的新药既昂贵又耗时，耗资10亿美元，耗时15年。这个过程不够快或灵活，无法跟上新的或耐药的传染病。为了应对新的传染病和病原体耐药性的威胁，需要采取一种新的方法，集中于新的药物靶点和方法，并增加投资，病原体致病的能力与这种微生物对它所感染的宿主的适应程度直接相关。高度适应宿主的病原体的一个例子是结核分枝杆菌，它已经进化到逃避，然后驻留在人体免疫系统的细胞中，人体对抗感染的主要手段。此外，存在与Mtb相关的细菌，其也是人类病原体，其主要折磨免疫缺陷患者，导致肺部和皮肤疾病。这些非结核分枝杆菌（NTM）由于缺乏特异性治疗和多重耐药性而难以治疗。该项目将使用一组化学化合物，由于它们与代谢物相似，因此选择它们，这些代谢物是细菌中容易发现的小分子物质。将针对结核分枝杆菌和三种非结核分枝杆菌对该化合物组进行测试，以确定影响生长的化合物。将对活微生物进行详细的尖端研究，以确定这些化合物如何干扰细菌过程。最后，将确定化合物的生物靶点，并确定相互作用的特征，以确定这些是否适合未来的药物发现工作。分枝杆菌对化合物的敏感性将为识别新药的新方法提供比较信息。

The threat posed to human life by infectious diseases cannot be underestimated, as the SARS-CoV-2 viral pandemic highlighted. Of the 56 million global deaths a year, 18% are due to infectious diseases. Mortality is not the only burden; the United Nations estimate the cost of the SARS-CoV-2 pandemic will be US$1 trillion. Secondary bacterial infections significantly impact during viral pandemics, as has been observed with first HIV and now SARS-CoV-2\.Tuberculosis, caused by the bacterium _Mycobacterium tuberculosis_ (Mtb), is the world's deadliest infectious disease, leading to 10 million cases and 1.6 million deaths per annum. Resistance of pathogens, the causative microorganisms of infectious disease, to drugs is a cause for grave concern. Drug-resistant Tuberculosis is predicted to cost the world $16.7 trillion by 2050\. Discovery of new drugs to treat infectious diseases is both expensive and time consuming, costing US$1 billion and taking 15 years. This process is not fast or agile enough to keep pace with new or resistant infectious diseases. A new approach, concentrating on novel drug targets and approaches, fuelled by more investment, is required to combat the threat of new infectious diseases and drug resistance of pathogens.The ability of a pathogen to cause disease is directly linked to how well this microorganism can adapt to the host it infects. An example of a highly host-adapted pathogen is Mtb, which has evolved to evade and then reside in the cells of the human immune system, the bodies primary means of combatting infections. In addition, there are bacteria that are related to Mtb that are also human pathogens, which predominantly afflict immunocomprised patients, leading to pulmonary and skin diseases. These Non-tuberculous Mycobacteria (NTM) are difficult to treat due to lack of specific treatments and multidrug resistance.This project will use a set of chemical compounds, selected due to their similarity to metabolites, small molecule substances that are readily found in bacteria. This compound set will be tested against Mtb and three NTMs to identify those that affect growth. Detailed, cutting-edge studies on live microbes will be carried out to identify how the compounds are interfering with bacterial processes. Finally, the biological targets of the compounds will be identified, and the interactions characterised to determine whether these are suitable for future drug discovery efforts. Sensitivity of the _Mycobacteria_ to the compounds will provide comparative information leading to identification of novel approaches for new drugs.