Developing novel antibiotics from natural products against resistant bacteria

抗菌素耐药性被世界卫生组织（世卫组织）确定为全球健康的十大威胁之一，威胁着我们治疗感染的能力，并导致多重耐药细菌的增加。随着耐药性在全球蔓延，目前使用的抗生素正变得越来越无效，新药的临床渠道也缺乏，只有六种新的抗微生物药物被列为针对世卫组织重点病原体清单的创新药物。当细菌等病原体发生突变时，就会产生抗微生物药物耐药性，从而获得导致对药物治疗产生耐药性的机制，从而使细菌感染更容易传播并难以治疗。碳青霉烯被保留为对抗多重耐药细菌的“最后手段”，然而碳青霉烯耐药细菌现在已经被发现，并且被世界卫生组织认为是一个关键的优先事项。对碳青霉烯类的抗性是细菌内b -内酰胺酶活性的结果，可以分为两类，要么使用丝氨酸残基，要么使用金属离子，即Zn2+，激活亲核水分子水解存在于b -内酰胺酶活性位点的药物的b -内酰胺环。虽然丝氨酸b -内酰胺酶抑制剂广泛用于与现有b -内酰胺类抗生素联合治疗以克服耐药性，但目前临床上还没有能够靶向金属b -内酰胺酶（MBL）的药物。通过靶向筛选，发现天然真菌产物曲霉酰胺a （Aspergillomarasmine a， AMA）既能抑制MBLs，又能协同恢复药物对耐药菌株的活性。基于AMA的结构活性关系，可以利用药物化学方法对AMA支架进行进一步的结构修饰。这些修饰可用于提高AMA的效力、选择性和其他类似药物的性质。因此，在这个项目中进行的研究旨在设计、合成和生物学评估使用基于ama的支架靶向金属b -内酰胺酶的新型抗菌剂。该项目的研究结果将有助于解决因抗微生物药物耐药性细菌显著增加而引起的重要全球健康问题。这项研究将重点放在新的MBL酶抑制剂上，从而产生新的潜在治疗方法，或为今后这类药物的研究奠定基础。因此，通过完成这项研究，我们将推进对耐药细菌的科学认识，并为耐药细菌的治疗提供可能的替代方案。

Identified by the World Health Organisation (WHO) as one of the top 10 threats to global health, antimicrobial resistance threatens our ability to treat infections and leads to the rise of multi-drug resistant bacteria. As drug-resistance spreads globally, the antibiotics in current use are becoming increasingly ineffective and the clinical pipeline for new drugs is lacking, with only six new antimicrobials being classed as innovative against the WHO's list of priority pathogens. Antimicrobial resistance occurs when pathogens such as bacteria mutate, resulting in gained mechanisms that lead to resistance against drug treatments, making bacterial infections easier to spread and difficult to treat. Carbapenems are reserved as a 'last resort' against multi-drug resistant bacteria, however carbapenem-resistant bacteria have now been identified and are deemed to be a critical priority by the WHO. Resistance to carbapenems is a result of B-lactamase enzyme activity within bacteria and can be split into two categories, either using a serine residue or a metal ion, i.e., Zn2+, that activates nucleophilic water molecules to hydrolyse the B-lactam ring of a drug present in the B-lactamases active site. Whereas serine B-lactamase inhibitors are widely available as part of a combination with existing B-lactam antibiotics to overcome resistance, there are currently no available drugs that are able to target metallo B-lactamase enzymes (MBL) clinically. Through targeted screening, it was found that a natural fungal product Aspergillomarasmine A (AMA), could inhibit MBLs and also synergistically restores the activity of drugs against resistant isolates.Based on AMA structure activity relationships, further structural modifications on the AMA scaffold can be made using medicinal chemistry approaches. These modifications can be used to improve potency, selectivity and other drug-like properties of AMA. As a result, the research to be conducted within this project is aimed at designing, synthesising and biologically evaluating novel antibacterial agents using an AMA-based scaffold to target metallo B-lactamases. The findings of this project will help to address important global health issues arising from the significant increase in antimicrobial-resistant bacteria. The study will focus on new MBL enzyme inhibitors, giving rise to new potential treatments or laying the foundations for future work on this class of drugs. As a result, by completing this research we will advance the scientific knowledge against antimicrobial-resistant bacteria and provide possible alternatives for treatment against drug-resistant bacteria.