Penicillin's Discovery and Antibiotic Resistance: Lessons for the Future?

Abstract

Undoubtedly, the discovery of penicillin is one of the greatest milestones in modern medicine. 2016 marks the 75th anniversary of the first systemic administration of penicillin in humans, and is therefore an occasion to reflect upon the extraordinary impact that penicillin has had on the lives of millions of people since. This perspective presents a historical account of the discovery of the wonder drug, describes the biological nature of penicillin, and considers lessons that can be learned from the golden era of antibiotic research, which took place between the 1940s and 1960s. Looking back at the history of penicillin might help us to relive this journey to find new treatments and antimicrobial agents. This is particularly relevant today as the emergence of multiple drug resistant bacteria poses a global threat, and joint efforts are needed to combat the rise and spread of resistance.

Keywords: Howard Florey; Penicillin; antimicrobial resistance.

Figure 1

The first mouse experiment and ceramic vessels which were used to grow the fungus. A. Results from the first penicillin trial experiment involving mice which was performed by the scientists at Oxford in 1940 (left panel). B. Old-fashioned bedpan, acquired from Radcliffe Infirmary hospital in Oxford to grow the first batch of penicillin. Ceramic culture vessel designed by Florey and colleagues to increase the yield of penicillin production (right panel). (Figures from [4]).

Figure 2

Schematic representation of the mechanism of penicillin action. PGN is composed of polysaccharide chains made of GlcNAc and MurNAc units (shown in different shades of blue) which in turn have small peptides attached to them. The transpeptidase enzyme (PBP) (in brown) catalyzes the formation of cross-linkages between these peptides, by specifically binding the last two D-alanine residues of one peptide (red circles). Penicillin mimics the structure of these residues and inactivates the PBP by forming an irreversible covalent bond to the catalytic serine residue of the enzyme [69].

Figure 3

Chemical structures of different classes of penicillins. Examples of different generations of penicillins are shown. Beta-lactam ring, the common feature of all classes, is highlighted in brown and the corresponding chemical substitute on the side chain is color-coded: blue, penicillin G (benzylpenicillin class, 1st generation); yellow, methicillin (2nd generation); green, ampicillin (aminopenicillin class, 3rd generation); orange, carbenicillin (carboxypenicillin class, 4th generation); purple, azlocillin (ureidopenicillin class, 4th generation).

Figure 4

The journey of antibiotic development and resistance. Key dates for introduction of different penicillin classes and corresponding emergence of resistance are shown (top and bottom, respectively). Examples of different generations of penicillin are indicated and color-coded as in Figure 3.