Antibiotics Red Biotechnology

Black Death

25 million people died between 1347 and 1352

Learning Outcomes

1.  To describe antibiotics and explain their discovery 2.  To understand the general mechanisms of action by

antibiotics 3.  To explain how antibiotic resistance develops and its

implication 4.  To recommend practical solutions that counter antibiotic

resistance

Learning Outcome #1

1.  To describe antibiotics and explain their discovery

What Are Antibiotics

•  Medicines used to treat and prevent bacterial infection

How Where They Discovered

Learning Outcomes

2.  To understand the general mechanisms of action by antibiotics

How Do They Work?

Learning Outcomes #3-4

3.  To explain how antibiotic resistance develops and its implication

4.  To recommend practical solutions that counter antibiotic resistance

Antibiotic Resistance Levy. 2020. J. Antimicrob. Chemother. 49: 25-30.

Evolution of Drug Resistance Penicillin was discovered by Alexander Fleming in 1928, and in1940, several years before the introduction of penicillin as atherapeutic, a bacterial penicillinase was identified by twomembers of the penicillin discovery team (1). Once the anti-biotic was used widely, resistant strains capable of inactivatingthe drug became prevalent, and synthetic studies were under-taken to modify penicillin chemically to prevent cleavage bypenicillinases (!-lactamases). Interestingly, the identificationof a bacterial penicillinase before the use of the antibiotic cannow be appreciated in the light of recent findings that a largenumber of antibiotic r genes are components of natural micro-bial populations (43). Which came first, the antibiotic or resis-tance?

In the case of streptomycin, introduced in 1944 for the treat-ment of tuberculosis (TB; “The Great White Plague”), mutantstrains of Mycobacterium tuberculosis resistant to therapeuticconcentrations of the antibiotic were found to arise duringpatient treatment. As other antibiotics have been discoveredand introduced into clinical practice, a similar course of eventshas ensued. Figure 1 shows the sequence of discovery andresistance development for the major classes of antibiotics.The unexpected identification of genetically transferable anti-biotic resistance in Japan in the mid-1950s (initially greetedwith skepticism in the West) (39) changed the whole picture byintroducing the heretical genetic concept that collections ofantibiotic r genes could be disseminated by bacterial conjuga-tion throughout an entire population of bacterial pathogens(with a few notable exceptions) (58, 72).

Only in the past few years has it been appreciated that geneexchange is a universal property of bacteria that has occurred

throughout eons of microbial evolution. The discovery of thepresence of putative bacterial gene sequences in eukaryoticgenomes has heightened awareness of the great importance ofhorizontal gene transfer (HGT) in genome evolution. Subse-quently, other aspects of gene transfer have been revealed bythe identification and distribution of genomic islands carryinggenes for pathogenicity (69) and other functional gene clustersin different bacterial genera. Not surprisingly, plasmid-medi-ated transfer of antibiotic resistance has been a major focus ofinvestigation because of its medical and, more recently, prac-tical significance (100).

SUPERBUGS AND SUPERRESISTANCE

Many of the bacterial pathogens associated with epidemicsof human disease have evolved into multidrug-resistant(MDR) forms subsequent to antibiotic use. For example,MDR M. tuberculosis is a major pathogen found in both de-veloping and industrialized nations and became the 20th-cen-tury version of an old pathogen. Other serious infectionsinclude nosocomial (hospital-linked) infections with Acineto-bacter baumannii, Burkholderia cepacia, Campylobacter jejuni,Citrobacter freundii, Clostridium difficile, Enterobacter spp., En-terococcus faecium, Enterococcus faecalis, Escherichia coli, Hae-mophilus influenzae, Klebsiella pneumoniae, Proteus mirabilis,Pseudomonas aeruginosa, Salmonella spp., Serratia spp., Staph-ylococcus aureus, Staphylococcus epidermidis, Stenotrophomo-nas maltophilia, and Streptococcus pneumoniae. The term “su-perbugs” refers to microbes with enhanced morbidity andmortality due to multiple mutations endowing high levels of

FIG. 1. History of antibiotic discovery and concomitant development of antibiotic resistance. The dark ages, the preantibiotic era; primordial,the advent of chemotherapy, via the sulfonamides; golden, the halcyon years when most of the antibiotics used today were discovered; the leanyears, the low point of new antibiotic discovery and development; pharmacologic, attempts were made to understand and improve the use ofantibiotics by dosing, administration, etc.; biochemical, knowledge of the biochemical actions of antibiotics and resistance mechanisms led tochemical modification studies to avoid resistance; target, mode-of-action and genetic studies led to efforts to design new compounds; genomic/HTS,genome sequencing methodology was used to predict essential targets for incorporation into high-throughput screening assays; disenchantment,with the failure of the enormous investment in genome-based methods, many companies discontinued their discovery programs. Other milestonesin this history include the creation of the FDA Office of New Drugs after the thalidomide disaster led to stricter requirements for drug safety,including the use of antibiotics. This slowed the registration of novel compounds. Before antibiotics were discovered, Semmelweis advocated handwashing as a way of avoiding infection; this practice is now strongly recommended as a method to prevent transmission.

VOL. 74, 2010 REFLECTIONS ON RESISTANCE 419

Davies and Davies. 2010. Microbio Mol Bio Rev. 74: 417–433.

Post-Antibiotic Era

Review on Antimicrobial Resistance. Antimicrobial Resistance: Tackling a Crisis for the Health and Wealth of Nations. 2014

Group Work

1.  Identify how each of the 4 groups has contributed to antibiotic resistance.

2.  Propose a solution (for each group) to address the problems identified in #1. Compose a slogan that can capture your idea.

Submit in 1 whole sheet of paper.

Slogan Rubrics

5 4 3 2 Strategy Creative,

logical and feasible strategy to address the issue

Logical and feasible strategy to address the issue

Some improvement needed in the logic or feasibility of strategy

Strategy is not logical and feasible

Use of Words Very effective use of words and captures the intended strategy

Effective use of words and captures the intended strategy

Use of words needs improvement but captures the intended strategy

Use of words not effective and does not capture the intended strategy