The evolving role of chemical synthesis in antibacterial drug discovery

Abstract

The discovery and implementation of antibiotics in the early twentieth century transformed human health and wellbeing. Chemical synthesis enabled the development of the first antibacterial substances, organoarsenicals and sulfa drugs, but these were soon outshone by a host of more powerful and vastly more complex antibiotics from nature: penicillin, streptomycin, tetracycline, and erythromycin, among others. These primary defences are now significantly less effective as an unavoidable consequence of rapid evolution of resistance within pathogenic bacteria, made worse by widespread misuse of antibiotics. For decades medicinal chemists replenished the arsenal of antibiotics by semisynthetic and to a lesser degree fully synthetic routes, but economic factors have led to a subsidence of this effort, which places society on the precipice of a disaster. We believe that the strategic application of modern chemical synthesis to antibacterial drug discovery must play a critical role if a crisis of global proportions is to be averted.

Keywords: antibiotics; chemical synthesis; drug discovery; semisynthesis.

Figure 1

Number of new antibacterials approved by the FDA in 5-year periods from 1983 to present.^[3]

Figure 2

Early history of antibiotics discovery and development.

Figure 3

Human chemical evolution of semisynthetic cephalosporin antibiotics (defining structural features of each generation are highlighted in blue).

Figure 4

Human chemical evolution of tetracycline and macrolide antibiotics by semisynthesis (important new structural features of each generation are highlighted in blue).

Figure 5

Milestones in the development of fully synthetic antibacterials, 1940–1969.

Figure 6

Milestones in the development of fully synthetic quinolone antibacterials, 1960–1999.

Figure 7

Milestones in the development of fully synthetic β-lactam antibiotics.

Figure 8

Development of fully synthetic oxazolidinone antibacterials.

Figure 9

Antibacterial natural products with potential for improvement for human use through the development of practical, fully synthetic routes.

Figure 10

Antibacterial natural products with potential for improvement for human use through the development of practical, fully synthetic routes.

Scheme 1

Chemical synthesis of salvarsan and prontosil.

Scheme 2

Fully synthetic approaches to penicilin V and 6-aminopenicillanic acid.^[23]

Scheme 3

The origins of antibacterial semisynthesis.

Scheme 4

Semisynthesis of 7-aminocephalosporanic acid (7-ACA) from cephalosporin C.

Scheme 5

Chemical innovations in tetracycline semisynthesis (important new structural features of each generation are highlighted in blue).

Scheme 6

Chemical innovation in macrolide semisynthesis.

Scheme 7

Chemical innovations enable development of semisynthetic ketolide antibiotics.

Scheme 8

Chemical synthesis of chloramphenicol and trimethoprim.

Scheme 9

A fully synthetic route to the natural carbapenem thienamycin, the precursor to the fully synthetic antibiotic imipenem.

Scheme 10

Key steps of a fully synthetic route to a C1-β-methyl carbapenem (Merck, 1984).

Scheme 11

Development of fully synthetic tetracycline antibacterials (novel structural features that could not be introduced by semisynthesis are highlighted in red).