Killing bacteria from within: In search of novel antibiotic targets

正如SARS-CoV-2病毒大流行所突显的那样，传染病对人类生命构成的威胁不容低估。在全球每年5600万人的死亡中，18%是由传染病造成的。死亡并不是唯一的负担；联合国估计，SARS-CoV-2大流行的成本将达到1万亿美元。在病毒大流行期间，继发性细菌感染会产生重大影响，正如在最初的艾滋病毒和现在的SARS-CoV-2中所观察到的那样。由结核分枝杆菌（Mtb）引起的结核病是世界上最致命的传染病，每年导致1 000万例病例和160万人死亡。病原体（传染病的致病微生物）对药物的耐药性是一个令人严重关切的问题。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。这一过程不够快速或灵活，无法跟上新的或耐药传染病的步伐。需要有一种新的方法，在更多投资的推动下，集中于新的药物靶点和方法，以对抗新传染病的威胁和病原体的耐药性。病原体致病的能力直接与这种微生物适应它所感染的宿主的能力有关。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，然后居住在人体免疫系统的细胞中，而人体免疫系统是对抗感染的主要手段。此外，还有一些与结核分枝杆菌有关的细菌也是人类病原体，主要影响免疫功能低下的患者，导致肺病和皮肤病。这些非结核分枝杆菌（NTM）由于缺乏特异性治疗和多药耐药而难以治疗。该项目将使用一组化合物，选择这些化合物是因为它们与代谢物相似，代谢物是细菌中容易发现的小分子物质。这组化合物将对结核分枝杆菌和三种ntm进行测试，以确定哪些影响生长。将对活微生物进行详细的前沿研究，以确定这些化合物是如何干扰细菌过程的。最后，将确定化合物的生物学靶点，并对其相互作用进行表征，以确定它们是否适合未来的药物发现工作。分枝杆菌对这些化合物的敏感性将提供比较信息，从而确定新药的新方法。

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.