Thursday, October 26, 2017

Waging war on microbes

The sentences "You have a viral infection? You should take antibiotics!" has always been an anathema to microbiologists. However, this thread of logic is surprisingly commonplace. Therefore, before delving into the history of antibiotics it is important to set the record straight. Antibiotics usually are used to treat bacterial infections. Therefore, antibiotics are completely ineffective against viruses, which are inhibited by antiviral drugs. The discovery of antimicrobial drugs was based on the underlying principle of microbial war- in nature microbes are always battling each other in order to dominate a particular habitat. Sometimes this entails secreting toxic molecules that can destroy other microbes, clearing the playground for the the host microbe to dominate. Thus, some of earliest antibiotics were discovered when scientists chanced upon these molecules and then used them to combat bacterial infections.

The earliest records of treating microbial infections date back to ancient Egypt in 1500 BC. By trial and error, they discovered that bread that had been infected by fungus could be used to cure bacterial infections. As disgusting as this may sound, this treatment was commonplace all over the world: Greeks in 16th century BC would use fungus scraped from cheese to treat wounded soldiers, the Chinese used moldy soya beans, and aborigines in Australia used mold that grew in the shade of eucalyptus trees. A more palatable source of antibiotics was discovered in the 1990s during the investigation of Nubian mummies. These mummies, dated back to 350-550 AD, contained the antibiotic tetracycline in their bones. This antibiotic, named because of it's four-ringed structure was produced from contaminating Streptomyces bacteria which grew in beer; the bacteria were competing against the yeast that was also present in the beer, leading to the production of the antibiotic.

Figure 1: The fungus responsible for moldy bread, Aspergillus species, as viewed under a microscope. Aspergillus is still used to produce antibiotics. Interestingly, this bacteria was given its name because its shape resembles a holy water sprinkler (aspergillum). Source.

The systematic search for antibiotics began with the observation that bacteria could be stained with certain dyes. Therefore, it could be argued that if dyes could enter bacterial cells, there were chemicals which do the same and could be used to kill bacteria. In 1889, Paul Ehrlich, a German physician, pursued this thread of logic to search for such bactericidal chemicals. In 1900 he hypothesized the concept of a magic bullet, a compound that could be used to only kill bacteria without damaging the human body. After several trials, he was successful in finding the first magic bullet in 1909; the compound Salvarsan, meaning saving arsenic, was very effective in curing syphilis, which is caused by the bacteria Treponema pallidum. Although this drug became an instant success around the world, it was controversial because it was thought to promote promiscuity. Furthermore, because of the serious side effects, Ehrlich was accused of criminal negligence in what came to be known as the Salvarsan Wars. Another famous synthesized antibiotic, Prontosil, was developed in 1932. This antibiotic was the first sulfonamide drug. Unlike Salvarsan, Prontosil and other sulfa drugs were effective against a wide range of infectious bacteria, which was why they remained popular well into World War II. In fact, the dependance of the German troops on these drugs ultimately tipped the balance of the war in favor of the Allied troops as discussed below.

Figure 2: Salvarsan was also known as compound 606 because it was sixth in the sixth group of chemicals that were synthesized for testing their antibiotic activity. Source.

The antagonism between mold and bacteria was observed by several scientists in the 19th century who recognized specific strains of fungi, such as Penicillium that is used to produce cheese, would also be resistant to bacterial contamination. The specific molecule, penicillin, that was responsible for this inhibition was recognized in 1928 by Alexander Fleming, a Scottish physician. The discovery of penicillin is best described by the quote "Chance favors the prepared mind" by Louis Pasteur, another giant in the field of microbiology. The story is that Fleming was on the search for a compound that could inhibit the growth of bacteria. To this end, he was studying the properties of staphylococci, a group of bacteria that frequently colonize the skin and upper respiratory tract of animals resulting in infections. Fleming's lab was frequently untidy, and as a result some of the cultures of the bacteria were contaminated by a fungus. He noticed that the bacterial colonies that were close to the fungus were killed, but those further away remained normal. Upon seeing this he famously remarked "That's funny", an expression that has probably been used by countless scientists over the years whenever they have made interesting discoveries. Fleming identified the fungus as being a Penicillium species, and after some months of calling the inhibitor by the eloquent name of "mould juice", renamed the molecule as penicillin. Unfortunately, he could not characterize penicillin further because he lacked the knowledge and skill required to do so. He was helped by Howard Florey, an Australian pharmacologist, and Ernst Chain, a British biochemist. Florey and Chain studied the therapeutic action of penicillin and discovered how to concentrate the active ingredient in penicillin that was responsible for its killing action. Subsequently all three of them received the Nobel Prize for Physiology or Medicine in 1945 for their work on penicillin.

Figure 3: A vintage advertisement. Interestingly, there are several online recipes for homemade penicillin for the enthusiastic chemists. Disclaimer: do not attempt it unless there's an apocalypse. Source.

Later Florey's research team attempted to mass produce penicillin, a herculean task because massive volumes of the fungal cultures needed to be grown to get a reasonable yield of the drug. Inspired by Florey's work, several companies in the U.S. and the United Kingdom began working on producing penicillin with the objective of having enough supplied for the D-day invasion of Europe. Finally, the mass production of penicillin was successfully standardized by the Northern Regional Research Laboratory (NRRL) in Peoria, Illinois. Following this, the United States had an unlimited supply by 1944, which was one of the reasons why the Allied troops had an advantage over the Germans, who were content with using sulfa drugs and therefore did not invest much effort in the production of penicillin. The "wonder drug" was far superior to any of the drugs that were available at the time and thousands of Axis troops died from wound infections and venereal diseases that were easily cured by penicillin. Interestingly penicillin saved the life of Hitler after a botched assassination attempt left him wounded; his physician at the time was aware of the effects of penicillin and could therefore treat Hitler. 

Following the discovery of penicillin, several new classes of antibiotics were discovered between the 1950s and the 1970s. These antibiotics are categorized based on their chemical structure, the bacteria they target, and their mechanism of action. Unfortunately the era of antibiotic discovery went into a hiatus and after almost 40 years, the new classes of antibiotics were discovered only in the late 2000s and early 2010s. The primary reason for this seemingly reduced pace in innovation is that previously antibiotics were discovered by testing the inhibitory activity of various chemical compounds. Therefore, the lower hanging fruits were already known and it became harder to find new and effective chemicals. Furthermore, even the latest antibiotics that were discovered in the 2000s belonged to antibiotic classes that already been described between 1950 and 1970. This underscores the main problem with antibiotic discovery- limited chemical diversity among antibiotics; they must be able to enter the bacteria and they should not be pumped out of the bacteria, which excludes a wide array of chemicals. A second problem is the ability of bacteria to gain resistance to antibiotics. Bacteria have the astounding capability of mutating the pathways that are targeted by antibiotics and thus gain resistance. To further complicate the situation, bacteria can then pass on this information to other bacteria via horizontal gene transfer leading to a further increase in antibiotic resistance in the bacterial population. These antibiotic resistant strains, also called "superbugs", have become thus become progressively harder to treat. Each year about 25,000 patients in the EU and more than 63,000 patients in the U.S. die from infections caused by multidrug-resistant bacterial infections. 

Figure 4: The causes and consequences of antibiotic resistance. Antibiotics were introduced in livestock to prevent infections that result due to the high animal densities. However, by 2001 it was discovered that almost 90% of the antimicrobials in the U.S. were being used for agriculture. The Food and Drug Administration is currently working to reduce the use of antibiotics to the bare minimum levels.  Source.

So how can we combat the growing incidences of drug-resistant bacteria? "The first rule of antibiotics is try not to use them, and the second rule is try not to use too many of them" is an excellent lesson mentioned in The ICU Book. This adage is an important step in reducing the instances of antibiotic resistance. Self-prescription, incorrect prescription, such as using antibiotics to combat viral infections, and overuse of antibiotics all contribute to an increase in resistant bacterial strains. Additionally, there have been several measures that have been taken by the scientific community to address the problems of antibiotic discovery and combat the emergence of drug resistant bacteria. These measures can be classified into different categories: changing the targets of the antibiotics, using novel chemicals or other agents to target bacteria, and preemptive measures to combat infections. Historically, antibiotic synthesis has followed a pattern: an accidental discovery followed by an investigation of the inhibitory/killing action in order to pinpoint bacterial targets, which include the cell wall, the machinery involved in DNA and protein synthesis, to name a few. However, it is now possible to identify several novel targets in the bacteria and design the antibiotic accordingly. The caveat is that these targets need to be essential to the bacteria so that they cannot be mutated easily. Alternatively, there have been attempts at developing antibiotics that target various cellular processes simultaneously, which will also reduce the probability of developing resistance as the likelihood of bacteria mutating all of these pathways at the same time is very low. There have also been attempts at using investigating chemicals from plants as a potential source of antibiotics. Plants produce several compounds that have demonstrated antibacterial activity. Another bacterial enemy that can be used are phages- viruses that have evolved to target bacteria. Unlike some antibiotics that indiscriminately kill bacteria, phages can be used to only kill the pathogenic strains leaving the other useful bacteria unaffected. As mentioned in a previous blog, vaccines can also be used to prime the body to stave off infections thereby reducing the need for antibiotics. Thus the war between science and bacterial invaders rages on. 


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