But so far, little has reached serious development. In fact, since those last discoveries in the 1980s, there has been a great deal of creative, rational, technologically cutting-edge screening for and efforts at design of new antibacterials. Not especially innovative, but it worked. Fig.1 1 (with the exception of trimethoprim, monobactams, fosfomycin, and carbapenems) were serendipitous, made by screening fermentation products or chemicals for inhibition of bacterial growth (empirical screening). Is the void due to a lack of innovation? While the simple definition of innovation is the act of introducing something new, the word implies creativity, intent, and experimentation. While there are a small number of novel compounds in the early clinical phase that might portend the end of this hiatus, in most cases their eventual developmental success is unclear.
There is a discovery void of unknown extent rather than a gap. (Fig.1) 1) of dates of discovery of distinct classes of antibacterials (as opposed to dates of introduction) illustrates that there have been no (as yet) successful discoveries of novel agents since 1987. The latest registered representatives of novel antibacterial classes, linezolid, daptomycin, and the topical agent retapamulin, were indeed introduced in 2000, 2003, and 2007, respectively, but these chemical classes (oxazolidinones, acid lipopeptides, and pleuromutilins) were first reported (or patented) in 1978 ( 124), 1987 ( 86), and 1952 ( 275), respectively. Walsh has noted that “no major classes of antibiotics were introduced” between 19 and refers to the interim as an innovation gap ( 115, 378). Even if unlimited money were poured into discovery and problematic regulatory guidelines were improved and stabilized, then it is probable that novel discovery would still be stymied because scientific obstacles remain to be overcome. If new molecular entities with desirable properties and specificity had been discovered commonly throughout the past 25 years, it seems likely that large pharmaceutical companies (Big Pharma) would have viewed the area as productive and continued with antibacterial discovery. While it is easy to find compounds that kill bacteria, it is hard to find novel antibacterial classes worthy of development. An underlying thesis of this review is that the bleak picture of antibacterial discovery is due to an expenditure of effort and resources on non-rate-limiting steps of the process. Rate-limiting steps to the discovery process are discussed, and some perspective on avenues to address those limitations is offered.
This review focuses on the scientific challenges to the discovery of novel small-molecule antibacterials rather than on the commercial and regulatory considerations, which are well covered in a number of reviews ( 186, 197, 301, 303, 345). The challenges to antibacterial discovery have kept the output of novel antibacterial drug classes to extraordinarily low levels over the past 25 years, even though discovery programs have been in place at large and small pharmaceutical companies as well as academic laboratories over this period.
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