Members of each antibiotic class share a common core structure, or scaffold. For example, the cephalosporins share a β-lactam embedded in a fused 4,6-ring system (). Most chemical scaffolds from which today’s antibiotics are derived were introduced between the mid-1930s and the early 1960s (). Aside from the introduction of carbapenems in 1985, all antibiotics approved for clinical use between the early 1960s and 2000 were synthetic derivatives of existing scaffolds. Just four such scaffolds—cephalosporins, penicillins, quinolones, and macrolides—account for 73% of the antibacterial new chemical entities filed between 1981 and 2005 (10
Fig. 2 Synthetic tailoring is widely used to create successive generations of antibiotic classes. Scaffolds are colored black; peripheral chemical modifications are colored red. The quinolone scaffold is synthetic, while the other scaffolds are natural products. (more ...)
Between 1962 and 2000, no major classes of antibiotics were introduced.
During synthetic tailoring (), the core of the antibiotic is left intact, preserving its activity, but the chemical groups at its periphery are modified to improve the drug’s properties. New generations are often designed to be active against pathogens that have become resistant to the previous generation. For example, second- (11
) and third-generation (12
) cephalosporins like cefaclor and ceftazidime are more resistant to destruction by the resistance enzyme beta-lactamase, and they can penetrate the Gram-negative outer membrane more effectively. When new beta-lactamases emerged that can cleave third-generation cephalosporins, pharmaceutical companies developed fourth-generation molecules like cefepime, which are less susceptible to cleavage by these enzymes (13
). Cephalosporins and other semisynthetic antibiotics account for 64% of the new chemical entities filed between 1981 and 2005 (10
), suggesting that incremental synthetic tailoring of natural scaffolds has become the predominant mode of antibiotic discovery. The most useful scaffolds have therefore been those that are easy for medicinal chemists to tailor; this allows many derivatives to be synthesized and tested for improved properties.
Organic synthesis plays two other key roles in antibiotic discovery. First, scaffolds like the quinolones and oxazolidinones are derived entirely from chemical synthesis; these fully synthetic scaffolds account for an additional 25% of the antibiotic NCEs. Second, some natural scaffolds like carbapenems can now be produced entirely by organic synthesis, expanding the scope of accessible scaffold modifications.
The interplay between semisynthesis and total synthesis—and the ability of synthetic modifications to unlock the therapeutic potential of a scaffold—are exemplified by the tetracyclines. Resistance to this class of 30S-targeting antibiotics is mediated in part by a widely distributed gene encoding an efflux pump. Semisynthetic modifications to the tetracycline scaffold yielded the glycylcycline tigecycline (14
). This third-generation molecule () is no longer a substrate for the efflux pump, restoring its activity against tetracycline-resistant pathogens. A fully synthetic route to the tetracyclines (15
) makes it possible to modify scaffold positions that difficult to modify semisynthetically, further broadening the range of accessible derivatives.
Making incremental improvements to existing scaffolds is a good short-term strategy for refilling the antibiotic pipeline, but a presumably more sustainable way to combat resistance is to discover new scaffolds. Their utility will depend on three criteria: spectrum of activity against Gram-positive and Gram-negative pathogens, lack of cross-resistance to existing drugs, and amenability to generations of synthetic tailoring.