Site author Richard Steane
The BioTopics website gives access to interactive resource material, developed to support the learning and teaching of Biology at a variety of levels.
Types of antibiotics
Click below to jump to the following categories of antibiotics:
, Tetracyclines, Quinolones, Aminoglycosides, Sulfonamides
- Beta-lactams prevent bacteria from constructing a cell wall, by binding to PBP (Penicillin-binding proteins) which are enzymes inside bacterial cells involved in the final stages (cross-linking of the peptide subunits) in the synthesis of peptidoglycan, which is the major component of bacterial cell walls.
- Contain a beta-lactam 'ring' which attaches to the active site of the bacterial enzymes.
It is known that Alexander Fleming discovered penicillin by chance in 1928 when a mould grew on bacterial culture plates which he had not cleared away.
He named the substance penicillin after identifying the mould as a Penicillium, and showed its effect on a variety of bacteria, but he could not develop the techniques necessary to culture the mould and extract the penicillin. With the stimulus of the second world war, Ernst Chain and Edward Abraham, together with Norman Heatley, working under Howard Florey, took up the challenge and worked out how to grow the mould and concentrate penicillin.
In 1945 Fleming, Chain and Florey were awarded the Nobel Prize for medicine.
Fleming was elected FRS in 1943 and knighted in 1944.
Interestingly, in 1921 Fleming had discovered the antibacterial enzyme lysozyme which is in egg white, tears and some other body secretions when he added nasal mucus to a bacterial culture plate.
- Penicillins are based on a chemical substance produced by the mould Penicillium notatum
- They are β-Lactams containing a nucleus of 6-aminopenicillanic acid (lactam plus thiazolidine ring) and other ring side-chains
- Most have "-cillin" on the end of their name
- Subdivided into spectra according to their target organism
- Mostly used against Gram-positive bacteria, but attempts have been made to extend their effectiveness
- Some have been developed semi-synthetically with different side-chains to give different properties: oral administration rather than by injection, or to avoid breakdown by bacterial penicillinase (beta lactamase) enzymes produced by penicillin-resistant bacterial strains
- Side-chains may contribute to side effects e.g. allergic reaction
- Some have been used in combination with a non-antibiotic compound with a similar structure to penicillin, that acts as an inhibitor of bacterial penicillinase
- However MRSA has developed resistance to methicillin, flucloxacillin and other penicillins by also having an altered penicillin-binding protein.
(ureidopenicillins and carboxypenicillins)
| Staphylococci and Streptococci
|Staphylococci (sensitive strains only), Haemophilus influenzae, Salmonella, Listeria, and Group A streptococci
|bacteria to left, and possibly Klebsiella
|bacteria to left, and possibly Pseudomonas spp (Gram negative)
Benzylpenicillin (penicillin G), Phenoxymethylpenicillin (penicillin V)
Methicillin, Cloxacillin, Flucloxacillin, Dicloxacillin
(amoxicillin plus clavulanic acid, a non-antibiotic compound with a similar structure to penicillin that acts as an inhibitor of penicillinase produced by penicillin-resistant bacterial strands)
|azlocillin, mezlocillin , piperacillin, carbenicillin* , ticarcillin*
* likely to be used in conjunction with a penicillinase inhibitor
In 1945, Giuseppe Brotzu isolated a fungus Cephalosporium acremonium from seawater near a sewage outflow in Cagliari, Sardinia, and showed that it killed Salmonella typhi. Unable to develop it further, he passed the fungal culture to the Oxford group resposible for penicillin. Edward Abraham extracted several cephalosporins, and used money from patenting them for several charitable purposes. Abraham was elected FRS in 1958, awarded CBE in 1973 and knighted in 1980.
- Cephalosporins are based on a chemical substance produced by the mould Cephalosporium acremonium
- β-Lactams containing 7-aminocephalosporanic acid nucleus
and sidechain containing 3,6-dihydro-2H-1,3-thiazine rings
- Most have "Ceph-" or "cef- " at the beginning of their name
- Subdivided into (five) "generations" according to their target organism
- Initially used against Gram-positive bacteria, but later versions increasingly used against a wider range of pathogens (and less effective against Gram-positives)
- Less susceptible to penicillinases, but bacteria with extended-spectrum beta-lactamase (ESBL) have caused problems
- Some have been developed with a variety of side-chains in order to avoid breakdown by bacterial beta lactamase enzymes produced by penicillin-resistant bacterial strains, or to attach to different PBPs, to pass the blood brain barrier, and ionise to facilitate entry into Gram-negative bacterial cells.
Moderate spectrum - "PEcK"
against Proteus mirabilis, Esherichia coli, Klebsiella pneumoniae
Moderate spectrum with anti-Haemophilus activity - "HEN"
against Haemophilus influenza, Enterobacter aerogenes, Neisseria
Second generation cephamycins
Moderate spectrum with anti-anaerobic activity
Broad spectrum with anti-Pseudomonas activity
Broad spectrum with enhanced activity against Gram positive bacteria and ß-lactamase stability
Antipseudomonal and less susceptible to development of resistance
Discovered in 1979 as a result of "a novel screening procedure", this class of antibiotics were named (monocyclic bacterially produced beta - lactams) and developed by Sykes et al, workers at the Squibb Institute for Medical Research New Jersey.
Only real example: aztreonam.
- Monobactams are based on a chemical substance produced by the bacterium Chromobacterium violaceum.
- Contain beta-lactam ring alone, not fused to another ring: based on 3-AMA (3 aminomonobactamic acid) - chemically similar to 6-APA
- Strong activity against susceptible gram-negative bacteria, including Pseudomonas aeruginosa
- Effective against a wide range of bacteria including Citrobacter, Enterobacter, E. coli, Haemophilus, Klebsiella, Proteus, and Serratia species
- No useful activity against gram-positive bacteria or anaerobes
- Must be injected or inhaled
This is a group of about 6 antibiotics released from 1985 and seen as our last effective defence against multi-resistant bacterial infections, but carbapenem resistance itself is now a cause for concern.
- Carbapenems are based on a chemical substance produced by the actinomycete Streptomyces cattleya
- Similar in structure to the penicillins, but with a carbon atom in position 1 instead of sulphur (hence the name)
- Most have "-penem" on the end of their name
- Broadest antibacterial spectrum of beta-lactams - active against both Gram-positive and Gram-negative bacteria, and anaerobes
- One of the antibiotics of last resort for many bacterial infections, and
mainstay of therapy in patients with serious hospital-acquired infection
- Must be injected
- Carbapenem antibiotic resistance is a recent scare story originating from Asia
- Carbapenem resistance due to genes on plasmids can be passed amongst different species
Imipenem + Cilastin (to prevent kidney damage)
In 1952 erythromycin was isolated by Eli Lilly's research team, led by J. M. McGuire, from the metabolic products of a strain of fungus Saccharopolyspora erythraea found in Filipino soil samples.
- Macrolides act as bacterial protein synthesis inhibitors
- Bind to the bacterial ribosome, preventing addition of amino acids to polypeptide chains
- Based on a chemical substance produced by the actinomycete Saccharopolyspora erythraea
- 14-, 15-, or 16-membered macrocyclic lactone rings
with unusual deoxy sugars L-cladinose and D-desosamine attached
- Difficult to synthesise chemically
- Most have "-omycin" on the end of their name
- Different compounds produced by substitution of side groups onto erythromycin
- Antimicrobial spectrum slightly wider than that of penicillins
- May be used for people who have an allergy to penicillins
- Used at lower doses, may reduce inflammation by adjusting the immune response
- May build up in the body due to liver recycling it into bile
- Streptococcus pneumoniae and other species have developed resistance to macrolides.
In 1945, at the age of 73, Benjamin Duggar discovered chlortetracycline (Aureomycin), the first of the tetracycline antibiotics, from a soil bacterium growing in allotment soil. Several major drug companies tried to develop and patent similar compounds but accommodated one another with cross-licencing.
In late 1958, the U.S. government charged Pfizer and American Cyanamid with price fixing in connection with tetracycline and witholding information, but lost the final appeal in 1982.
- Tetracyclines act as bacterial protein synthesis inhibitors
- Bind to the bacterial ribosome, preventing addition of amino acids to polypeptide chains
- Based on chemical substances produced by various Streptomyces species
- 4 hydrocarbon rings
- Most have "-cycline" on the end of their name
- Some naturally produced, some semi-synthetic - produced by substitution of side groups
- Side effects sometimes cause problems
- May be used in the control of other non-microbial parasites in malaria and elephantiasis
- Food reduces the absorption of tetracycline, so it should be taken at least two hours before or after meals
- Originally quite a wide antimicrobial spectrum but resistance is now a problem
Nalidixic acid was discovered in the early 1960s during research
of antimalarial agents - it was a by-product of the synthesis of chloroquine.
Since then, more than 10,000 analogues and derivative compounds have been developed and more than 800 million patients have been treated with quinolones.
- Quinolones interfere with DNA replication and transcription in bacteria
- Synthetic chemotherapeutic antibacterial compounds containing the quinolone nucleus or the naphthyridone nucleus, both ring structures
- Many have "-oxacin" on the end of their name (fluoroquinolones: "-floxacin")
- All synthetic
- Development has produced four generations, with extra ring structures and substituents, extending their antimicrobial spectrum, particularly versus anaerobic bacteria
- Side effects e.g. toxicity sometimes cause problems
- Numerous pathogens now exhibit resistance worldwide.
Selman A. Waksman,
professor of biochemistry and microbiology at Rutgers University New Jersey USA, was interested in screening soil micro-organisms and led a team that discovered over twenty antibiotics, as well as coining the term antibiotic! He was credited with the discovery of streptomycin, which was greatly used against Mycobacterium tuberculosis.
In fact he had little to do with it; it was Albert Schatz, then a 23-year old graduate student in his laboratory, returning from war duty and inspired to find an antibiotic to treat tuberculosis, who first isolated streptomycin in 1943, essentially working in isolation.
After the major commercial success of streptomycin, Schatz had to sue Waksman in order to be (at least partially) credited with the discovery. In 1994, Schatz was awarded the Rutgers medal for his work on developing streptomycin.
From patent income, Waksman established a foundation for microbiological research, which established the Waksman Institute of Microbiology located at Rutgers University.
He was awarded the 1952 Nobel Prize in Physiology or Medicine "for the discovery of streptomycin".
- Aminoglycosides act as bacterial protein synthesis inhibitors
- Compounds of (usually 3) amino-sugars connected by glycosidic bonds
- Some derived from bacteria of the Streptomyces genus (with the suffix -mycin) or Micromonospora, ( suffix -micin).
- Side effects e.g. ototoxicity sometimes cause problems
Sulphonamides/sulfonamides (sulpha/sulfa drugs)
Although these are antibacterial or antimicrobial, they are often described as chemotherapeutic rather than antibiotic because they are synthesised chemically. Some sulphonamides are not antibacterial and have other medical functions e.g. diuretics, anti-glaucoma agents, anticonvulsants.
In 1932 the first antibacterial sulphonamide drug, a red azo-dye called Prontosil, was found to be active against bacterial infections in mice, but it did not show antibacterial activity on its own in the laboratory. It was later found that it was converted into sulfanilamide (bioactivated) which was active and Prontosil was described as a prodrug.
- The sulphonamide group acts as an analogue of PABA (para-amino benzoic acid) which is involved in folate synthesis, thus starving the bacteria of the B-group vitamin folate.
- Sulfanilamide (an intermediate in the dye-making industry) has several clinical disadvantages which can be reduced by adding different sidechains.
- Possible side effects include hypersensitivity (allergic reactions), liver and kidney damage.
In contrast to the chance discovery of sulpha drugs, a compound with a similar mode of action, Trimethoprim, was developed by Gertrude Belle Elion and George H. Hitchings. In a long career involving nucleic acid metabolism, Elion and Hitchings introduced chemical treatments for several diseases. They concentrated on biochemical differences between normal and diseased human body cells and pathogenic bacteria and viruses and investigated compounds that block metabolic pathways.
Together with Sir James W. Black, Elion and Hitchings gained the Nobel Prize in Physiology or Medicine.
In 1956 Dr. E. C. Kornfeld, organic chemist at Eli Lilly, isolated vancomycin (as compound 05865) from a soil sample containing Streptomyces orientalis from the Borneo jungle.
Examples: vancomycin, teicoplanin, telavancin, bleomycin, ramoplanin, and decaplanin
- glycopeptides are produced in fermentation by various micro-organisms
- prevent bacterial cell wall synthesis (different mechanism to penicillin)
- structure: glycosylated .. cyclic or polycyclic .. nonribosomal peptides
- most include amino acids differing from the normal 20 in proteins, perhaps connected by bonds other than peptide or disulfide bonds
- used against Gram-positive microorganisms
- toxicity of early isolates ("Mississippi mud" - contained impurities) slowed down early development
- the related compound avoparcin (animal "growth promoter" produced by Cyanamid) has stimulated development of resistance (not in USA, banned in Europe in 1997, recently dropped in Australia)
- Vancomycin-resistant enterococci (VRE) emerged in the mid-1980s
- Vancomycin-resistant Staphylococci emerged in the mid-1990s
- Vancomycin and related compounds were considered as drugs of last resort for treating MRSA
Oxazolidinones are heterocyclic organic compounds, some of which were found to have antibiotic properties in the mid 1980s. Since resistance to other types of antibiotics had become a problem, these compounds were given special attention.
Linezolid is one such compound that came to prominence in 1996 and was approved by the FDA in 2000, but most patents expired in 2015.
- entirely synthetic
- based on the 5-membered oxazolidinone ring containing both nitrogen and oxygen
- act as protein synthesis inhibitors
Other oxazolidinone antibiotics are currently being developed.
It is interesting that most of the recent discoveries in the field of antibiotics have been peptides with a looped molecular structure.
In the late 1980s, researchers at Eli Lilly and Company investigated the compound LY 146032 - later named Daptomycin - produced by the soil saprotroph Streptomyces roseosporus.
However it was not further developed until Cubist Pharmaceuticals acquired the rights to it in 1995 and under the name Cubicin it was approved by the US FDA in 2003 for use against complicated skin and skin structure infections (cSSSI).
Daptomycin is a lipopeptide:
- It has a 13-member amino acid chain, 10 of which form into a loop
- Several of these are unusual - non proteinogenic; others are D-forms (rather than the normal L-forms which are usually found in proteins)
- Some amino acids are hydrophobic (lipophilic) and act together with a decanoyl (10 carbon) hydrocarbon side-chain
- The lipophilic daptomycin tail inserts itself into the bacterial cell membrane, and alters its shape/curvature
- This causes rapid membrane depolarization and loss of potassium ions
Other lipopeptides also have antibiotic or antifungal properties.
In January 2015 Dr. Kim Lewis, director of Northeastern University's Antimicrobial Discovery Center, announced the discovery of teixobactin, a new antibiotic that bacteria will possibly not become resistant to for decades. It was produced by a new organism, within the class β-proteobacteria, Eleftheria terrae, isolated from soil from Maine, USA following the adoption of a novel technique.
This development involved a large team of specialist workers at different sites in the USA, Germany and UK.
The isolation technique involved iChips - isolation chips - multiple small diffusion chambers buried in soil for weeks, so as to absorb environmental growth factors.
Colonising microorganisms eventually adapted for growth under otherwise prohibitive in vitro conditions in the lab.
Several thousand isolates were screened for antibiotic production: teixobactin emerged as the most promising out of 25 'possibles', patented by NovoBiotic Pharmaceuticals, Cambridge, Massachusetts, USA.
- is a depsipeptide - a molecule that has both peptide and ester linkages in proximity in the same amino acid chain
- is produced in 'normal' fermentation process following acclimatisation to standard microbiological techniques
- prevents bacterial cell wall synthesis - by targeting bacterial lipids, not proteins
- consists of a peptide chain of 11 amino acids, with a square loop at the end
- has 2 out of 11 amino acids different from the normal 20 in proteins, and loop formed by ester bond
- shows considerable promise against Gram-positive microorganisms and also TB
- is active against MRSA and other bacterial strains resistant to other antibiotics
- is unlikely to become useless as quickly as other antibiotics due to the development of bacterial resistance to it
More on this website about the isolation technique
In July 2016 Andreas Peschel and Bernhard Krismer announced a 'novel' antibiotic which they called lugdunin.
It was produced by a commensal organism, Staphylococcus lugdunensis, isolated from the human nasal cavity.
This organism was first described in 1988 but it has occasionally been implicated in causing some infections.
The discovery of the compound and the elucidation of its structure involved a team of specialist workers at the University of Tübingen, Germany.
This followed the observation that human nasal colonisation by S. lugdunensis was associated with a significantly reduced S. aureus carriage rate
They conclude that human microbiota should be considered as a source for new antibiotics.
- is a cyclic peptide - a ring-shaped molecule composed of amino acids linked by peptide bonds
- consists of a loop of 6 amino acids, one incorporating a thiazolidine group
- is built from mostly fairly normal amino acids, but several are D-forms (rather than the normal L-forms which are usually found in proteins)
- is active against Staphylococcus aureus - a common commensal species in the nasal cavity, also MRSA and other bacterial strains resistant to other antibiotics
Antibiotic ApocalypseBBC Panorama TV programme
Antibiotics timeline From Wikipedia, the free encyclopedia
Penicillin From Wikipedia, the free encyclopedia
Amoxicillin From Wikipedia, the free encyclopedia
The True Story of the Discovery of Streptomycin by Albert Schatz
Notebooks Shed Light on an Antibiotic's Contested Discovery
By PETER PRINGLE
Nuffield trust looks at prescribing patterns for antibiotics, both in England and internationally.
The fluoroquinolones: structures, mechanisms of action and resistance, and spectra of activity in vitro.
J S Wolfson and D C Hooper
Linezolid from National Institute for Health and Care Excellence (NICE)
The Nobel Prize in Physiology or Medicine 1988
Sir James W. Black, Gertrude B. Elion, George H. Hitchings
Norine (database of nonribosomal peptides)
A new antibiotic kills pathogens without detectable resistance - a 21-author paper on Teixobactin in Nature
From Wikipedia, the free encyclopedia
Daptomycin: a lipopeptide antibiotic for the treatment of serious Gram-positive infections
In vitro and in vivo activity of LY 146032, a new cyclic lipopeptide antibiotic.
Daptomycin biosynthesis in Streptomyces roseosporus: cloning and analysis of the gene cluster and revision of peptide stereochemistry
Human commensals producing a novel antibiotic impair pathogen colonization 17-author paper on Lugdunin in Nature
Staphylococcus lugdunensis: the coagulase-negative staphylococcus you don't want to ignore
Too much of a good thing The Daily Telegraph