Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Lab, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodzki St., PL-20093 Lublin. Poland.
Department of Applied Pharmacy, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 1 Chodzki St., PL-20093 Lublin. Poland.
Curr Med Chem. 2017;24(18):1948-1982. doi: 10.2174/0929867323666161213102127.
Infectious diseases are one of the most important and urgent health problems in the world. According to the World Health Organization (WHO) statistics, infectious and parasitic diseases are a cause of about 16% of all deaths worldwide and over 40% of deaths in Africa. A considerable progress that has been made during last hundred years in the fight against infectious diseases, in particular bacterial infections, can be attributed mainly to three factors: (1) the general improvement of living conditions, in particular sanitation; (2) development of vaccines and (3) development of efficient antibacterial drugs. Although considerable progress in reduction of the number of cases of bacterial infections, especially in lethal cases, has been made, continued cases and outbreaks of these diseases persist, which is caused by different contributing factors. Indeed, during last sixty years antibacterial drugs were used against various infectious diseases caused by bacterial pathogens with an undoubtable success. The most fruitful period for antibiotic development lasted from 40's to 60's of the last century and resulted in the majority of antibiotics currently on the market, which were obtained by screening actinomycetes derived from soil. Although the market for antibacterial drugs is nowadays greater than 25 billion US dollars per year, novel antibacterial drugs are still demanded due to developed resistance of many pathogenic bacteria against current antibiotics. In the last five years, one can observe a dramatic increase in cases of resistant bacteria strains (e.g. Klebsiella pneumoniae and E. coli) which are responsible for difficult to treat pneumonia and infections of urinary tract. The development of resistant bacteria strains is a side effect of antibiotic application for treatment: the infections become untreatable as a result of the existence of antibiotic-tolerant persisters. In this review, we discuss the challenges in antibacterial drug discovery, including the molecular basis of drug resistance, drug targets for novel antibacterial drugs, and new compounds (since year 2010) from different chemical classes with antibacterial activity, focusing on structure-activity relationships.
传染病是世界上最重要和最紧迫的健康问题之一。根据世界卫生组织（WHO）的统计，传染病和寄生虫病是全球所有死亡人数的约 16%和非洲所有死亡人数的 40%以上的原因。在过去的一百年中，在对抗传染病（特别是细菌感染）方面取得了相当大的进展，可以主要归因于三个因素：（1）生活条件的普遍改善，特别是卫生条件的改善；（2）疫苗的发展；（3）高效抗菌药物的发展。尽管在减少细菌感染病例，特别是致命病例方面取得了相当大的进展，但这些疾病的持续病例和爆发仍然存在，这是由不同的促成因素造成的。事实上，在过去的六十年中，抗菌药物被用于对抗由细菌病原体引起的各种传染病，取得了无可置疑的成功。抗生素开发最富有成效的时期是在上世纪 40 年代到 60 年代，由此产生了目前市场上的大多数抗生素，这些抗生素是通过筛选土壤来源的放线菌获得的。尽管目前抗菌药物的市场每年超过 250 亿美元，但由于许多病原菌对现有抗生素的耐药性不断发展，仍需要新型抗菌药物。在过去的五年中，人们可以观察到耐药菌菌株（例如肺炎克雷伯菌和大肠杆菌）的病例急剧增加，这些菌株导致难以治疗的肺炎和尿路感染。耐药菌菌株的发展是抗生素治疗应用的副作用：由于存在抗生素耐受的持久性菌，感染变得无法治疗。在这篇综述中，我们讨论了抗菌药物发现所面临的挑战，包括耐药性的分子基础、新型抗菌药物的药物靶点以及自 2010 年以来具有抗菌活性的不同化学类别的新化合物，重点介绍了结构-活性关系。
