Strategic paradigm shifts in the antimicrobial drug discovery process of the 21st century
Strategic paradigm shifts in the antimicrobial drug discovery process of the 21st century
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DOI：
10.2174/187152607782110040
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发表时间：
2007-09-01
影响因子：
--
通讯作者：
Quadri, Luis E. N.
中科院分区：
文献类型：
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作者：
Quadri, Luis E. N.
由对单一和多种抗菌药产生抗药性的细菌菌株产生的全球感染数量正在上升。伴随着这一令人震惊的上升趋势，制药公司开发新型抗菌剂的意图和决心出现了明显的下降趋势。面对21世纪由不断升级的抗菌素耐药性问题带来的公共卫生挑战，迫切的目标之一是开发一种新的化疗药物。这里讨论了药物发现过程中两个相互关联的战略范式转变，预计这两个转变将有助于实现这一目标。其一是抗菌药物向抗感染药物(ATA)范式的转变。另一种是从以基本目标偏好标准为主导的目标候选优先排序范式转变为依赖较少限制性标准的替代范式，该标准不排除有条件的基本目标。开发抗感染药物的条件基本靶标的例子包括参与小分子毒力效应物生物合成的酶，如非核糖体肽-聚酮衍生的清除铁的铁载体。铁载体被许多病原菌利用来吸收铁，包括分枝杆菌和耶尔森氏菌。本文综述了铁载体生物合成抑制剂的最新研究进展。
The numbers of global infections produced by bacterial strains that are resistant to single and multiple antimicrobial drugs are on the rise. Concomitant with this alarming upward trend, there is a clear downward trend in the intent and determination of pharmaceutical companies to develop novel antimicrobials. One of the pressing goals to confront the twenty first century's public health challenges brought about by the escalating antibacterial drug resistance problem is the development of an armamentarium of new chemotherapeutic agents. Two interconnected strategic paradigm shifts in the drug discovery process that are anticipated to facilitate the achievement of this goal are discussed herein. One is an antimicrobial to anti-infective (ATA) paradigm shift. The other is a shift from a target candidate prioritization (TCP) paradigm that is dominated by an essential target preference criterion to an alternative paradigm that relies on a less restrictive criterion, one that does not exclude conditionally essential targets. Examples of conditionally essential targets for the development of anti-infectives include the enzymes involved in the biosynthesis of small-molecule virulence effectors such as non-ribosomal peptide-polyketide-derived iron-scavenging siderophores. Siderophores are utilized for iron uptake by many pathogenic bacteria, including Mcobacterium and Yersinia species. The recent progress towards developing inhibitors of siderophore biosynthesis is discussed herein.