The Rise and Fall of Antibiotics

Over the past 90 years, antibacterial discovery has gone from boom to bust.

For about 30 years in the middle of the 20th century, pharmaceutical companies regularly churned out new classes of the drugs, many of which doctors still use today, such as penicillin and the tetracyclines. However, by the 1980’s, discovery slowed and companies started leaving the field, drawn by the rise of profitable drugs in other therapeutic areas. As a result, only one successful new class of antibacterial drugs has been discovered since the late 1980’s (bedaquiline). This is the story of antibiotic resistance, or the Rise and Fall of Antibiotics. With growing numbers of bacterial strains resistant to existing drugs, pharmaceutical experts have been at a loss to know what to do. The success of early antibiotics saved many lives. It was reported in 1951 for example, thanks to drug treatment, the pneumonia mortality rate dropped by 50% in the previous decade. The antibacterial development boom started after the discovery in 1943 of streptomycin, the first antibiotic to treat tuberculosis.

Albert Schatz and his supervisor Selman A. Waksman, found the compound in Streptomyces bacteria. Streptomyces lives in soil, and soon pharmaceutical companies in the U.S., Europe and Japan started screening soil microbes. These companies were tapping into a microbial war that had been going on for many centuries in the soil. In a typical screening program, company microbiologists would obtain soil samples from across the globe. When soil samples came in, the microbiologists would first isolate the many different microbes present and then grow them separately in liquid cultures. The resulting broths were tested to see whether they could stop the growth of a particular pathogen, such as Staphylococcus aureus or Escherichia coli. If they did, then the real work began of isolating the active molecule. From the 1940’s to the 1960’s, companies improved this method and discovered about 20 major antibacterial classes, including the tetracyclines, the macrolides and the glycopeptide vancomycin. As scientists studied the major classes, they found how the antibacterials worked. The ß-lactams, such as penicillin and cephalosporin, inhibited cell wall synthesis. Tetracyclines, macrolides, and aminoglycosides affect protein synthesis. and the quinolones disrupted DNA replication. Medicinal chemists played a significant role in the boom by developing antibiotics with improved properties. Beecham Research Laboratories, an English Company that became part of GSK, produced several important derivatives of penicillin. An example was methicillin, developed in 1959, had a 2,6-dimethoxyphenyl side chain which shielded the compound from some some ß-lactamases, the enzymes that enable bacteria to resist penicillin. Discoveries of new classes started to taper off during the 1970’s. Companies started to see diminishing returns from their screening programmes. In the 1950’s, companies had to screen through around 1000 bacterial cultures to find a compound no one had seen before. To find Daptomycin, which was discovered in 1987, and is one of the last new classes to reach the market, scientists had to pick through about 10 million cultures. The rise and fall of antibiotics was upon us. In the late 1990’s, the industry tried to improve antibacterial discovery by turning to genomics. When the genome of Haemophilus influenzae was publicized in 1995, companies such as GSPK thought they could find new drugs by searching for genes essential for bacterial survival in multiple species. Then by using in vitro assays, they screened for compounds that inhibit the activity of associated proteins. The strategy failed for multiple reasons.

Reasons for Failure of the Genomic approach

First, it focused too much on single targets. Most successful antibacterial drugs targeted more than one bacteria. For example, beta-Lactams hit multiple proteins involved in cell wall synthesis. If a compound shuts down just one target, bacteria can easily mutate that gene and gain resistance to the drug.

The second problem was that chemists synthesized drugs on the basis of hitting targets inside and outside human cells. These rules were not helpful in targeting actual bacteria. Unlike human cells, gram-negative microbes have dual-membrane barriers and protein complexes that actively remove unwanted chemicals. Scientists currently do not understand what allows compounds to slip though these barriers.

With the failure of high volume screening, many companies shifted their emphasis to more lucrative therapeutic areas such as chronic diseases. Also worrying, was that many still effective drugs had lost patent protection, filling the market with cheap alternatives.

At the start of the 1980’s, more than 35 major US and European companies were working on antibacterial drugs. Now there are fewer than 10.

According to the Infectious Diseases Society of America (IDSA), 16 new antibacterial drugs were approved in the US between 1983 and 1987. In the past five years, only two have been approved.

While the supply of new drugs has been drying up, pathogens have been developing resistance to existing drugs. In 2013, the Centers for Disease Control & Prevention issued a warning about gram-negative pathogens called carbapenum-resistant Enterobacteriaceae (CRE). Carbapenums are drugs often used as a last resort in serious infections. One of every two patients with CRE in the bloodstream dies.

Experts think that the future of antibacterial treatments will depend on developing new strategies, and on luring pharmaceutical and biotech companies into the field [1].

Antibiotic Resistance is Widespread

For some pathogens, such as MRSA and Acinetobacter, physicians have turned to antibiotics abandoned decades ago because of toxic side effects. Several pathogens are close to becoming difficult to treat in some regions. Examples of pathogens that have become extensively resistant are:

Acinetobacter baumanii (Pneumonia and wound infections) resistant to all common drugs available.
Klebsiella pneumoniae (Pneumonia) resistant to carbapenen, fluoroquinolones, amino glycosides and cephalosporins in hospitals in many countries.
Mycobacterium tuberculosis (Tuberculosis) resistant to rifampicin, isoniazid, fluoroquinolone, kanamycin, amikacin, capreomycin on a wordwide scale, particularly Eastern Europe and South Africa.
Neisseria gonorrhoeae (Gonorrhea) resistant to penicillins, tetracyclines, fluoroquinolones, macrolides and cephalosporins in the Western Pacific and Japan.
Salmonella enterica (Food-borne bacteremia) resistant to Ampicillin, chloramphenicol, tertacycline, sulfamethoxazole, trimethoprim and fluoroquinolones on a wordwide scale.
Staphylococcus aureus (many types of infection) resistant to beta-lactams, fluoroquinolones and gentamycin on a worldwide scale.

Resistance Problems – a Perspective

Throughout history pathogens have attacked humans, and before the middle of the twentieth century we relied on our immune systems to survive these attacks. Many people died, but though improvements in diet, sanitation and water purification, our immune systems were strengthened. For other pathogens vaccines were developed, and insecticides used to control mosquitoes. However, our fear of pathogens was eliminated only by antibiotics. By taking pills for a few days, we could quickly recover fro most bacterial diseases.

Nowadays our resistance problems derive from the cumulative effect of several complex factors. One has been our cavalier attitude. Foe example, in 2009 an American supermarket chain began to advertise free antibiotics to attract customers. Whilst hospitals are beginning to oversee their own use of antibiotics, the agricultural community is largely uncontrolled after drugs are approved by government agencies. Outside of hospitals however, individual patients continue to insist on antibacterial treatments for viral infections which stimulates the emergence of resistant bacteria. It is clear that the educational effort needs to be intensified. Another factor is dosage – doses are kept low enough to cause few side effects, but high enough to kill susceptible cells. Conditions that control the growth of susceptible cells, but not that of mutants, are precisely the cause that leads to enrich mutants. In other words, conventional dosing strategies lead directly to the emergence of resistance [2].

1. Torrice, M. Antibacterial Boom and Bust, Chemical and Engineering News, September 2013, The American Chemical Society.
2. Drlica, K, and Perlin, D.S. Antibiotic Resistance, Understanding and Responding to an Emerging Crisis, Pearson Education, 2011.

With growing numbers of bacterial strains resistant to existing drugs, pharmaceutical experts have been at a loss to know what to do. The success of colloidal silver in treating a wide range of infections has led to the development of the PyraMed Colloidal Silver Generator. By using pure silver electrodes, distilled water, and software controlled electronics, a safe and reliable method of making an effective antibiotic at home is at hand.

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PyraMed Colloidal Silver Generators

Through the use of Microcontroller Technology, the production of colloidal silver of optimum concentration and particle size is now possible using the PyraMed Colloidal Silver Generator. Tests at the University of Leeds on Aquasilver, the pure form of colloidal silver produced by the PyraMed Colloidal Silver Generator has shown that particle size in the range 1-10 nm corresponds to nanometer size groups of atoms. These colloidal silver particles become suspended in distilled water to produce a colloid due to electrostatic charges produced by electrolysis, the safest method of production.

Electron Microscope Image of metallic silver particles produced by the PyraMed

Various methods of production of colloidal silver over the years have shown that the electrical method of using silver electrodes in water produces nano size particles, which become suspended to produce a colloid. Particle size is important, for example particles in the region of one to ten nano-meters in size are active in inhibiting the HIV virus from binding to host cells. PyraMed Colloidal Silver Generators have taken this process to a new level of effectiveness by the use of Microcontroller Technology. This means that the silver electrodes are controlled by software stored in the chip (known by electronic engineers as firmware). Gone are the days of two wires, crocodile clips and rows of batteries.

Robert Bows, EzineArticles Basic Author

The PyraMed Colloidal Silver Generator technology ensures that only distilled water is used, since the device measures the conductivity of the water before starting production. Some colloidal silver generator devices on the market do not discriminate about what kind of water us used, but this feature is important in the design philosophy of the PyraMed Colloidal Silver Generator. This is to ensure that the particles of silver do not combine with dissolved solids to produce silver salts (such as silver chloride). By using pure water and high purity silver electrodes, the production of pure colloidal silver is achieved (known as Aquasilver). In order to measure conductivity, the PyraMed Colloidal Silver Generator electrodes are arranged as a measurement ‘cell’, as well as forming part of the electrolysis process. When a voltage is applied between the electrodes, the current flowing depends on the dimensions of the cell, and the conductivity of the liquid. The cell dimensions and the applied voltage are stored as constants in an embedded equation written in C code which forms part of the firmware design.


During the production cycle, the PyraMed Colloidal Silver Generator is programmed to reverse the current flow in the silver electrodes according to an algorithm which takes into account the mobility of the silver particles. This ensures that the colloidal silver particles are deposited in sheet like formations in the liquid whose position creates an even distribution. For this reason, the PyraMed Colloidal Silver Generator production process is neither constant voltage nor constant current since the time constant determined by the algorithm varies according to concentration and other factors. There are several advantages to this method, one being that stirring becomes unnecessary, and also that the reversal of current flow produces an even wear of the electrodes.


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