Antibiotics

Theory

Many infections are attributed to the presence of bacteria that feed on the host body's resources and multiply. To determine how dangerous a bacterial infection is we look at how rapidly it multiplies, how many resources it consumes, how resilient it is against the body's immune system, and how easily it spreads from person to person.

Antibiotics are among the most common and effective medicines to fight bacterial infections. They are chemicals that inhibit or destroy the harmful bacteria while doing no damage to the host. Antibiotics can be synthetically created or produced by various forms of fungi and bacteria.

history

The first documented use of antibiotics to treat an infection was in 1871 by Joseph Lister. This was the use of penicillium glaucum to treat a wound his nurse had suffered. He first theorized that bacteria could be responsible for infections. French scientist Louis Pasteur and German scientist Robert Koch conducted separate studies of bacteria and proved the connection, setting the stage for modern antibiotics.

Italian scientist Bartolomeo Gosio discovered in 1893 that mycophenolic acid is the active ingredient in P. glaucum which makes it an antibiotic. The first synthetic antibiotic is Salvarsan, created by Paul Ehrlich and his collaborators. This was created specifically to treat Syphilis. Neosalvarsan was created in 1913 as a more effective and less dangerous form.

Prontosil was created in 1930 by German bacteriologist Gerhard Domagk. His experience in World War 1 inspired him to create this broad-spectrum antibacterial. Its use over time led to the discovery of antibiotic resistance from bacteria. Prontosil works by inhibiting nucleic acid synthesis, but a mutation in the target enzyme of the bacteria rendered Prontosil ineffective.

The use of Prontosil was superseded by Penicillin, the first fungus-produced antibiotic which was discovered inadvertently by Scottish bacteriologist Alexander Fleming. In 1929 he isolated the active molecule produced by the fungus. Penicillin can be mass-produced and was popular during World War 2.

The Golden Age of antibiotics lasted from the 1940s to the 1970s. 20 classes of antibiotics were discovered in this time with different mechanisms of action. Antibiotic resistance was easily resolved by using a different class of antibiotic. Since the 1970s no new classes of antibiotic have been discovered, so modern antibiotics are derivatives of already-existing agents. (Hutchings)

Targets

  • Cell Wall Synthesis

Gram-positive bacteria have thick cell walls as part of their cellular structure. Since human cells lack cell walls, this makes a safe target for antibiotics. Peptidoglycan is the key ingredient in bacterial cell walls, so the antibiotics inhibit peptidoglycan biosynthesis. This leaves the cell vulnerable to osmotic pressure (leaking/absorbing fluids) and autolysis (self-destruction).

  • Cell Membranes

Gram-negative bacteria have thin cell walls. Instead of peptidoglycan, lipopolysaccharides unique to gram-negative bacteria are targeted by antibiotics. When lipopolysaccharides are destroyed, the cell undergoes lysis (disintegration of the membrane).

  • Protein Synthesis

Ribosomes are free particles in the cell that link amino acids to create proteins. 70S ribosomes, also known as Svedburg units, are unique to bacteria. These consist of 50S and 30S subunits, either of which can be targeted by antibiotics in various ways.

  • Nucleic Acid Synthesis

RNA (Ribonucleic Acid) and DNA (Deoxyribonucleic Acid) are the types of nucleic acids.

Polymerase enzymes are responsible for the elongation of RNA in the cell. These are structurally different between bacteria and eukaryotic cells, so they can be safely targeted. Without RNA elongation, the bacterial cells are unable to decode the DNA or express the genes, leaving the cell stagnant and unregulated. 

Other antibiotics block DNA synthesis by inhibiting topoisomerases. These are responsible for DNA's ability to split and reseal. Without this ability, normal cell division is impossible, so the bacteria can't reproduce.

  • Metabolic Pathways

Anti-metabolites are competitive inhibitors of metabolic enzymes. The folic acid metabolic pathway is the target for antibiotics. The effect on bacterial cells depends on the antibiotic and what step in the pathway is being targeted. Either growth of the bacteria will be inhibited, or it will become bactericidal (self-destruct). (Uddin) 

Gram +/- Bacteria

antibiotic resistance

Due to the Law of Natural Selection, species will thrive or be extinguished according to their ability to survive in an environment. Bacteria struggling against antibiotics can develop mutations that render the antibiotic ineffective. These antibiotic-resistant bacteria thrive and may become more dangerous than before.

There are three mechanisms bacteria use to overcome antibiotics:

  • Destruction/Modification of an Antibiotic

This is especially effective against antibiotics which interfere with mechanisms inside the cell. The bacteria fight directly against the antibiotic by destroying it before it can accomplish its purpose.

  • Increased Efflux/Reduced Influx

Antibiotics must be absorbed by the bacteria in order to function. If the bacteria are able to efficiently block or eject the antibiotic, it will have little to no effect.

  • Modification of Drug Targets

To be safe and effective, antibiotics have unique and specific targets within the bacteria. Even minor changes to these targets can allow them to evade the antibiotic while still effectively performing their function for the cell.

Antibiotic resistance can be achieved through two methods:

  • Random Mutation

Minor changes in genetic code occur regularly as bacteria reproduce. In the presence of antibiotics, a coincidentally resistant bacteria will survive and reproduce while those around it are destroyed.

  • Plasmid Transfer

Plasmids are circular DNA molecules separate from the cell's chromosome. They perform no immediate function for the cell but can transfer mutations including antibiotic resistance between cells and even between species. (Warnes)

citations

Hutchings MI, Truman AW, Wilkinson B. Antibiotics: past, present and future. Curr Opin Microbiol. 2019 Oct;51:72-80. doi: 10.1016/j.mib.2019.10.008. Epub 2019 Nov 13. PMID: 31733401.

Warnes SL, Highmore CJ, Keevil CW. Horizontal transfer of antibiotic resistance genes on abiotic touch surfaces: implications for public health. mBio. 2012 Nov 27;3(6):e00489-12. doi: 10.1128/mBio.00489-12. PMID: 23188508; PMCID: PMC3509412.

Uddin TM, Chakraborty AJ, Khusro A, Zidan BRM, Mitra S, Emran TB, Dhama K, Ripon MKH, Gajdács M, Sahibzada MUK, Hossain MJ, Koirala N. Antibiotic resistance in microbes: History, mechanisms, therapeutic strategies and future prospects. J Infect Public Health. 2021 Dec;14(12):1750-1766. doi: 10.1016/j.jiph.2021.10.020. Epub 2021 Oct 23. PMID: 34756812.

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