In what stage of bacterial growth can penicillin inhibit the growth of the cellular wall?

The bacterial growth has 3 main stages: lag-phase, log-phase and stationary phase. I was wondering in which one of them penicillin can inhibit the growth of the cellular wall of bacteria and why. I was thinking that the respons would be lag and log phase, because at these points bacteria multiply the most, while in stationary phase most of the bacteria are in adult form with a well formed bacterial wall already, but I'm not quite sure.

This is a really good question that requires you to appreciate a few different details and to overcome a few implicit assumptions that you might perhaps have.

  • The bacterial growth stages you refer to only apply to a population of bacteria. Individual cells do not undergo these stages.
  • Relatedly, bacterial population growth stages are independent of the stage of bacterial cell wall growth.

You can have mature or immature bacteria at any stage of "bacterial growth", with either fully formed walls, or with none. This understanding should answer your question partially.

Here are a few more things to consider, for a more complete understanding:

  1. Penicillins are a class of molecules, of varying efficacy and bioavailability across the body and across different kinds of walls and membranes.
  2. Inhibiting the spread of bacteria can be achieved using two types of antibiotics… bactericidal or bacteriostatic ones. Bactericidal means the bacteria die, while bacteriostatic means their growth is slowed or stopped.
  3. Penicillins are bactericidal agents that exert their mechanism of action by inhibition of bacterial cell wall synthesis and by inducing a bacterial autolytic effect. So even mature bacteria will die off in the later stages of outgrowth. In principle, it does not matter what growth stage the bacteria are at, the bactericidal mechanism will take place regardless.
  4. Pencillins are more effective against Gram-positive bacteria. Gram-negative bacteria have a lipopolysaccharide and protein layer that surrounds the peptidoglygan layer of the cell wall, which acts as a barrier for the penicillin from reach its target (which is responsible for completing the synthesis of peptidoglycans, the structural component of bacterial cell wall). However, penicillin can get into Gram-negative cells, for example through channels called porins.

This is more or less very standard knowledge that is easy to look up. Wikipedia's entry on penicillin is a good place to orient yourself if you already haven't.

Penicillin is a beta lactam antibiotic that inhibits Transpeptidase enzyme ( Penicillin binding protein). Transpeptidase is required for the cross linking of murein monomers required for cell wall synthesis.

So as Penicillin binds to Transpeptidase it does not let it involved in cross linking of murein monomers and hence cell wall synthesis can't be completed. This is how Penicillin inhibits bacterial growth .

Now the phases ( lag ,log , stationary) you mentioned are used when a culture of bacterial colonies is grown and not used for a single bacterium .

How Antibiotic Resistance Happens

Antibiotics save lives but any time antibiotics are used, they can cause side effects and lead to antibiotic resistance.

Since the 1940s, antibiotics have greatly reduced illness and death from infectious diseases. However, as we use the drugs, germs develop defense strategies against them. This makes the drugs less effective.

Antimicrobials Treat Infections Caused by Microbes

Microbes are very small living organisms, like bacteria. Most microbes are harmless and even helpful to humans, but some can cause infections and disease. Drugs used to treat these infections are called antimicrobials. The most commonly known antimicrobial is antibiotics, which kill or stop the growth of bacteria.

Two Types of Microbes

  • Bacteria cause illnesses such as strep throat and food poisoning. Bacterial infections are treated with drugs called antibiotics (such as penicillin).
  • Fungi cause illnesses like athlete&rsquos foot and yeast infections. Fungal infections are treated with drugs called antifungals.

How Germs Become Resistant and Spread

  1. Germs (bacteria and fungi) are everywhere. Some help us. Some make people, crops, or animals sick. Some of those germs are resistant to antibiotics.
  2. Antibiotics kill germs that cause infections. But antibiotic-resistant germs find ways to survive. Antibiotics also kill good bacteria that protect the body from infection.
  3. Antibiotic-resistant germs can multiply. Some resistant germs can also give their resistance directly to other germs.
  4. Once antibiotic resistance emerges, it can spread into new settings and between countries.

Germ Defense Strategies

Antibiotics fight germs (bacteria and fungi). But germs fight back and find new ways to survive. Their defense strategies are called resistance mechanisms. Bacteria develop resistance mechanisms by using instructions provided by their DNA. Often, resistance genes are found within plasmids, small pieces of DNA that carry genetic instructions from one germ to another. This means that some bacteria can share their DNA and make other germs become resistant.

Examples of Defense Strategies for Germs

Germs can use defense strategies to resist the effects of antibiotics. Here are a few examples.

Resistance Mechanisms (Defense Strategies)
Resistance Mechanisms
(Defense Strategies)
Restrict access of the antibiotic Germs restrict access by changing the entryways or limiting the number of entryways.

Example: Gram-negative bacteria have an outer layer (membrane) that protects them from their environment. These bacteria can use this membrane to selectively keep antibiotic drugs from entering.

Example: Some Pseudomonas aeruginosa bacteria can produce pumps to get rid of several different important antibiotic drugs, including fluoroquinolones, beta-lactams, chloramphenicol, and trimethoprim.

Example: Klebsiella pneumoniae bacteria produce enzymes called carbapenemases, which break down carbapenem drugs and most other beta-lactam drugs

Example: Some Staphylococcus aureus bacteria can bypass the drug effects of trimethoprim

Example: Escherichia coli bacteria with the mcr-1 gene can add a compound to the outside of the cell wall so that the drug colistin cannot latch onto it.

Penicillium: Description, Structure and Reproduction

Penicillium is a saprophytic fungus, com­monly known as blue or green mold. According to Raper and Thom (1949), the genus includes 1 36 species, distributed throughout the world. They are present in soil, in air, on decaying fruits, vegetables, meat, etc.

The “wonder drug” penicillin was first dis­covered by Sir Alexander Fleming at Sant Mary’s Hospital, London, in 1929 during his work with a bacterium Staphylococcus aureus responsible for boil, carbuncle, sepsis in wounds and burns etc., get contaminated with mold spore (Penicillium notatum) which after proper growth causes death of 5. aureus showing lytic zone around itself.

He isolated and called this anti­microbial compound as Penicillin. Later Raper and Alexander (1945) selected a strain of P. crysogenum, more efficient than P. notatum, in the production of penicillin. The importance of Penicillium is mentioned in the Table 4.6.

Vegetative Structure of Penicillium:

The vegetative body is mycelial (Fig. 4.42A, B). The mycelium is profusely branched with septate hyphae, composed of thin-walled cells containing one to many nuclei (Fig. 4.42C). Each septum has a central pore, through which cyto­plasmic continuity is maintained.

Some mycelia grow deeper into the substratum to absorb food material and others remain on the substrate and grow a mycelial felt. The reserve food is present in the form of oil globules.

Reproduction in Penicillium:

Penicillium reproduces by vegetative, asexual and sexual means.

1. Vegetative reproduction:

It takes place by accidental breaking of vegetative mycelium into two or more fragments. Each fragment then grows individually like the mother mycelium.

2. Asexual Reproduction:

Asexual repro­duction takes place by unicellular, uninucleate, nonmotile spores, the conidia formed on conidiophore (Fig. 4.43).

The conidiophore develops as an erect branch from any cell of the vegetative mycelium. The conidiophore may be unbranched (P. spinulosum, P. thomii) or becomes variously branched (P. expansum). The branch of the conidiophore (Fig. 4.44B) is known as ramus (plural rami) which further becomes branched known as metulae. A number of flask-shaped phialid or sterigmata develops at the tip of each metulae.

Each sterigmata develops at its tip a number of conidia arranged basipetally (younger one near the mother and older one away from it). In species (P. spinulosum) with unbranched coni­diophore, the sterigmata develops at the tip of conidiophore. Rarely (P. claviforme) many conidiophores become aggregated to form a club- shaped fructification called coremium, which develops conidia known as coremiospores.

During the development of conidium, the tip of the sterigma swells up and its nucleus divides mitotically into two nuclei, of which one migrates into the swollen tip and by partition wall the swollen region cuts off from the mother and forms the uninucleate conidium.

The tip of the sterigma swells up again and following the same procedure second conidium is formed, which pushes the first one towards the outer side. This process repeats several times and thus a chain of conidia is formed.

The conidia (Fig. 4.44C) are oval, elliptical or globose in structure having smooth, rough, echinulate outer surface and of various colou­rations like green, yellow, blue etc.

After maturation, the conidia get detached from the mother and are dispersed by wind. On suitable substratum, they germinate (Fig. 4.44D) by developing germ tube. The nucleus undergoes repeated mitotic division and all nuclei enter into the germ tube. The septa formation continues with the elongation of germ tube and finally a new septate branched mycelium develops.

3. Sexual Reproduction:

Sexual reproduction has been studied only in few species (Fig. 4.44). It shows great variation from isogamy (P. bacillosporum), oogamy (P. vermiculatum) to somatogamy (P. brefeldianum). Most of the species are homothallic, except a few like P. luteum are heterothallic. Ascocarps are rarely formed. Based on the ascocarps, different genera can be assigned as Europenicillium, Talaromyces and Carpenteles.

The genus Talaromyces consists of 15 species. All the species of Talaro­myces studied are homothallic. The account of sexual reproduction deals with Talaromyces vermiculatus (= Penicillium vermiculatum) was described by Dangeard (1907). This spedes shows oogamous type of sexual reproduction. The female and male sex organs are ascogonium and antheridium’, respectively.

The ascogonium develops from any cell of the vegetative filament as an erect uninucleate and unicellular body (Fig. 4.44E). The nucleus then undergoes repeated mitotic divisions and produces 32 or 64 nuclei (Fig. 4.44F).

The antheridium develops simultaneously with the ascogonium from any neighbouring hypha (Fig. 4.44F). It is also an uninucleate and unicellu­lar branch which coils around the ascogonium. The apical region of antheridial branch cuts off by septum and forms a short, somewhat inflated uni­cellular and uninucleate antheridium (Fig. 4.44G).

After maturation of both ascogonium and antheridium, the tip of the antheridium bends and touches the ascogonial wall. The common wall at the point of contact dissoves and the two cytoplasm then intermixed.

The nucleus of the .antheridium does not migrate (Fig. 4.44H) into the ascogonium (Dangeard, 1907). Later, the pairing of nuclei into the ascogonium takes place by the ascogonial nuclei only. The ascogonium then divides by partition wall into many binucle­ate cells, arrange uniseriately (Fig. 4.44H).

Some of the binucleate cells of the ascogo­nium projects out by the formation of multicellu­lar ascogenous branched hyphae, whose cells are also dikaryotic (Fig. 4.441). The apical cells of the dikaryotic mycelia swell up and function as an ascus mother cells (Fig. 4.44J).

Both the nuclei of ascus mother cell undergo karyogamy and form diploid (2n) nucleus (Fig. 4.44K). The nucleus then undergoes first meiosis, then mito­sis, results in the formation of 8 nuclei those after accumulating some cytoplasm form 8 ascospores (Fig. 4.44L).

With the development of ascogonium and antheridium, many sterile hyphae gradually entangle with them and finally after the forma­tion of ascospores, the total structure becomes a round fruit body i.e., cleistothecium (Fig. 4.44M). The asci arrange irregularly inside the cleistothecium. The ascospores may be globose, elliptical or lenticular in shape with smooth, echinucleate, pitted (Fig. 4.44N) or branched outer wall like a pully-wheel in lateral view.

The ascospores are released by the dis­solution of ascus and cleistothecium wall. The ascospore germinates on a suitable substratum by developing germ tube (Fig. 4.440) and ulti­mately into a mycelium like the mother.

Bacterial growth occurs in 4 phases as described above. But, gram-positive bacteria are susceptible during the log phase of the bacterial growth. During log phase, bacteria are sensitive because

  • Bacteria grow exponentially and increase their cell mass.
  • The cell is small in size.
  • The cell produces its proteins, amino acids and other precursor units.
  • The cell membrane is less permeable at that time because the cell needs nutrient from the environment.
  • When nutrients are taken up by the cell, antibiotics also move inside the cell.
  • Penicillin when enter, it degrades its cell wall subunit.
  • Bacterial cell become weak and die
  • This phase is medically important as in this phase, bacteria are sensitive to drugs.

In what stage of bacterial growth can penicillin inhibit the growth of the cellular wall? - Biology

Here we consider the roles of antibiotics, with special focus on the clinically useful antibiotics that are used to control bacterial infections in humans. This page deals with 3 main topics:

The antibacterial effect of penicillin was discovered by Alexander Fleming in 1929. He noted that a fungal colony had grown as a contaminant on an agar plate streaked with the bacterium Staphylococcus aureus, and that the bacterial colonies around the fungus were transparent, because their cells were lysing. Fleming had devoted much of his career to finding methods for treating wound infections, and immediately recognised the importance of a fungal metabolite that might be used to control bacteria. The substance was named penicillin, because the fungal contaminant was identified as Penicillium notatum. Fleming found that it was effective against many Gram positive bacteria in laboratory conditions, and he even used locally applied, crude preparations of this substance, from culture filtrates, to control eye infections. However, he could not purify this compound because of its instability, and it was not until the period of the Second World War (1939-1945) that two other British scientists, Florey and Chain, working in the USA, managed to produce the antibiotic on an industrial scale for widespread use. All three scientists shared the Nobel Prize for this work, and rightly so - penicillin rapidly became the "wonder drug" which saved literally millions of lives. It is still a "front line" antibiotic, in common use for some bacterial infections although the development of penicillin-resistance in several pathogenic bacteria now limits its effectiveness (see later).

The action of penicillin is seen in Figure A. This shows an 'overlay plate', in which a central colony of the fungus Penicillium notatum was allowed to grow on agar for 5-6 days, then the plate was overlaid with a thin film of molten agar containing cells of the yellow bacterium, Micrococcus luteus. The production of penicillin by the fungus has created a zone of growth inhibition of the bacterium. This demonstration parallels what Alexander Fleming would have observed originally, although he saw inhibition and cellular lysis of the bacterium Staphylococcus aureus.

Figure B shows the typical asexual sporing structures of a species of Penicillium. The spores are produced in chains from flask-shaped cells (phialides) which are found at the tips of a brush-like aerial structure.

This morphogenetic effect of penicillin can be demonstrated by growing either Gram-positive or Gram-negative bacteria in the presence of sub-lethal concentrations of penicillin. The images below show Gram-stained cells of Bacillus cereus that had been cultured in the absence of penicillin (left-hand image) or in the presence of a low concentration of the penicillin derivative termed Ampicillin (right-hand image). By affecting the cross-linking of the bacterial cell wall, penicillin has caused the bacterium to grow as larger cells with less frequent cell divisions.

An expanded role for the penicillins came from the discovery that natural penicillins can be modified chemically by removing the acyl group to leave 6-aminopenicillanic acid (see diagram above) and then adding acyl groups that confer new properties. These modern semi-synthetic penicillins such as Ampicillin, Carbenicillin (see diagram) and Oxacillin have various specific properties such as:

  • resistance to stomach acids so that they can be taken orally,
  • a degree of resistance to penicillinase (a penicillin-destroying enzyme produced by some bacteria)
  • extended range of activity against some Gram-negative bacteria.

Although the penicillins are still used clinically, their value has been diminished by the widespread development of resistance among target microorganisms and also by some people's allergic reaction to penicillin.

The phenomenal success of penicillin led to the search for other antibiotic-producing microorganisms, especially from soil environments. One of the early successes (1943) was the discovery of streptomycin from a soil actinomycete, Streptomyces griseus. As shown in Figures C and D, actinomycetes are bacteria that produce branching filaments rather like fungal hyphae, but only about 1 micrometre diameter. They also produce large numbers of dry, powdery spores from their aerial hyphae.

Figure C. Edge of an agar colony of the actinomycete, Streptomyces griseus, viewed at low magnification (x10 objective of a compound microscope). Like all actinomycetes, this species grows as narrow filaments, with aerial branches that end in chains of spores. The spirally shaped aerial spore chains typical of the genus Streptomyces are seen in this image. Fig. D. Higher magnification of some of the aerial hyphae and spore chains.

Figure E. Agar plate showing inhibition of fungal growth by a contaminating colony of Bacillus species. Image supplied by IW Sutherland

Producer organism

Site or mode of action

Why are there so few clinically useful antibiotics?

Several hundreds of compounds with antibiotic activity have been isolated from microorganisms over the years, but only a few of them are clinically useful. The reason for this is that only compounds with selective toxicity can be used clinically - they must be highly effective against a microorganism but have minimal toxicity to humans. In practice, this is expressed in terms of the therapeutic index - the ratio of the toxic dose to the therapeutic dose. The larger the index, the better is its therapeutic value.

It will be seen from the table above, that most of the antibacterial agents act on bacterial wall synthesis or protein synthesis. Peptidoglycan is one of the major wall targets because it is found only in bacteria. Some of the other compounds target bacterial protein synthesis, because bacterial ribosomes (termed 70S ribosomes) are different from the ribosomes (80S) of humans and other eukaryotic organisms. Similarly, the one antifungal agent shown in the table (griseofulvin) binds specifically to the tubulin proteins that make up the microtubules of fungal cells these tubulins are somewhat different from the tubulins of humans.

Comparing the antibiotic sensitivity of different bacteria

Figure F. Antibiotic-sensitivity testing. Petri dishes were spread-inoculated with Staphylococcus albus (white growth) or Micrococcus luteus (yellow growth) before antibiotic assay "rings" were placed on the agar surface. The coloured disks at the end of each spoke of the rungs are impregnated with different antibiotics. Clockwise from the top (arrow) these are: Novobiocin, Penicillin G, Streptomycin (white disk), Tetracycline, Chloramphenicol, Erythromycin, Fusidic acid (green disk) and Methicillin. Clear zones of suppression of bacterial growth around the individual antibiotic disks are evidence of sensitivity to these antibiotics.

The diameter of the clear zone is related to the initial antibiotic concentration (which differs for the antibiotics on the ring), its solubility and its diffusion rate through agar. Standard tests performed on many bacteria by the manufacturers of these assay disks enable the diameter of the clearing zone to be related to the minimum inhibitory concentration (MIC) of each antibiotic for the strain being tested. The MIC can then be compared with the known tissue levels of these antibiotics when they are administered to patients, to assess whether the antibiotics would be effective for treatment of particular pathogens.

The repeated or continued use of antibiotics creates selection pressure favouring the growth of antibiotic-resistant mutants. These can be detected by comparing the size of clearing zones (or even the complete absence of clearing zones) of bacterial strains in plate assays such as those above. By the use of these disks it is also possible to detect the occurrence of individual mutant cells with antibiotic resistance in a culture of a strain that is sensitive to antibiotics. An example of this is shown in Figure G (below).

Figure G . Effects of different antibiotics on growth of a Bacillus strain. The right-hand image shows a close-up of the novobiocin disk (marked by an arrow on the whole plate). In this case some individual mutant cells in the bacterial population were resistant to the antibiotic and have given rise to small colonies in the zone of inhibition.

Antibiotic resistance is not a recent phenomenon. On the contrary, this problem was recognised soon after the natural penicillins were introduced for disease control, and bacterial strains held in culture collections from before "the antibiotic era" have also been found to harbour antibiotic-resistance genes. However, in some cases the situation has now become alarming, with the emergence of pathogenic strains that show multiple resistance to a broad range of antibiotics. One of the most important examples concerns multiple-resistant strains of Staphylococcus aureus in hospitals. Some of these strains cause serious nosocomial (hospital-acquired) infections and are resistant to virtually all the useful antibiotics, including methicillin, cephalosporins and other beta-lactams that target peptidoglycan synthesis, the macrolide antibiotics such as erythromycin and the aminoglycoside antibiotics such as streptomycin and neomycin, all of which target the bacterial ribosome. The only compound that can be used effectively against these staphylococci is an older antibiotic, vancomycin, which has some undesirable effects on humans. Recently, some clinical strains of S. aureus have developed resistance to even this compound.

Many of the antibiotic-resistance genes of staphylococci are carried on plasmids (see Agrobacterium for discussion of this) that can be exchanged with Bacillus spp. and Streptococcus spp., providing the means for acquiring additional genes and gene combinations. Some are carried on transposons - segments of DNA that can exist either in the chromosome or in plasmids. It is ironic, and tragic, that the bacterium S. aureus that opened the antibiotic era with Fleming's original discovery of 1929 could also be the first to become non-treatable with the huge battery of antibiotics discovered and developed over the last 60 years.

Antibiotic usage in agriculture: creating a reservoir of resistance genes?

One of the fiercest public debates at present concerns the use of antibiotics in agriculture and veterinary practice. The reason for concern is that the same antibiotics (or, at least, antibiotics with the same mode of action on bacteria) are also used for human therapy. Thus, it is possible that the irresponsible use of antibiotics for non-human use can lead to the development of resistance, which could then be passed onto human pathogens by transfer of plasmids. The greatest concern of all centres on the routine use of antibiotics as feed additives for farm animals - to promote animal growth and to prevent infections rather than to cure infections. It has been difficult to obtain precise figures for the amounts of antibiotics used in this way. But the scale of the potential problem was highlighted in a recent report by the Soil Association, which collated figures on the total usage of different types of antibiotic for humans and for animals:


There are a large number of PBPs, usually several in each organism, and they are found as both membrane-bound and cytoplasmic proteins. For example, Spratt (1977) reports that six different PBPs are routinely detected in all strains of E. coli ranging in molecular weight from 40,000 to 91,000. [3] The different PBPs occur in different numbers per cell and have varied affinities for penicillin. The PBPs are usually broadly classified into high-molecular-weight (HMW) and low-molecular-weight (LMW) categories. [4] Proteins that have evolved from PBPs occur in many higher organisms and include the mammalian LACTB protein. [5]

PBPs are all involved in the final stages of the synthesis of peptidoglycan, which is the major component of bacterial cell walls. Bacterial cell wall synthesis is essential to growth, cell division (thus reproduction) and maintaining the cellular structure in bacteria. [2] Inhibition of PBPs leads to defects in cell wall structure and irregularities in cell shape, for example filamentation, pseudomulticellular forms, lesions leading to spheroplast formation, and eventual cell death and lysis. [6]

PBPs have been shown to catalyze a number of reactions involved in the process of synthesizing cross-linked peptidoglycan from lipid intermediates and mediating the removal of D-alanine from the precursor of peptidoglycan. Purified enzymes have been shown to catalyze the following reactions: D-alanine carboxypeptidase, peptidoglycan transpeptidase, and peptidoglycan endopeptidase. In all bacteria that have been studied, enzymes have been shown to catalyze more than one of the above reactions. [3] The enzyme has a penicillin-insensitive transglycosylase N-terminal domain (involved in formation of linear glycan strands) and a penicillin-sensitive transpeptidase C-terminal domain (involved in cross-linking of the peptide subunits) and the serine at the active site is conserved in all members of the PBP family. [4]

Some low-molecular-weight PBPs associate with the MreB cytoskeleton and follow its rotation around the cell, inserting petipdoglycan in an oriented manner during cell growth. [7] In contrast, high-molecular-weight PBPs are independent from MreB and maintain cell wall integrity by detecting and repairing defects in the peptidoglycan. [8]

PBPs bind to β-lactam antibiotics because they are similar in chemical structure to the modular pieces that form the peptidoglycan. [9] When they bind to penicillin, the β-lactam amide bond is ruptured to form a covalent bond with the catalytic serine residue at the PBPs active site. This is an irreversible reaction and inactivates the enzyme.

There has been a great deal of research into PBPs because of their role in antibiotics and resistance. Bacterial cell wall synthesis and the role of PBPs in its synthesis is a very good target for drugs of selective toxicity because the metabolic pathways and enzymes are unique to bacteria. [10] Resistance to antibiotics has come about through overproduction of PBPs and formation of PBPs that have low affinity for penicillins (among other mechanisms such as lactamase production). These experiments change the structure of PBP by adding different amino acids into the protein, allowing for new discovery of how the drug interacts with the protein. Research on PBPs has led to the discovery of new semi-synthetic β-lactams, wherein altering the side-chains on the original penicillin molecule has increased the affinity of PBPs for penicillin, and, thus, increased effectiveness in bacteria with developing resistance.

The β-lactam ring is a structure common to all β-lactam antibiotics. [12]

How do antibiotics kill bacterial cells but not human cells?

In order to be useful in treating human infections, antibiotics must selectively target bacteria for eradication and not the cells of its human host. Indeed, modern antibiotics act either on processes that are unique to bacteria--such as the synthesis of cell walls or folic acid--or on bacterium-specific targets within processes that are common to both bacterium and human cells, including protein or DNA replication. Following are some examples.

Most bacteria produce a cell wall that is composed partly of a macromolecule called peptidoglycan, itself made up of amino sugars and short peptides. Human cells do not make or need peptidoglycan. Penicillin, one of the first antibiotics to be used widely, prevents the final cross-linking step, or transpeptidation, in assembly of this macromolecule. The result is a very fragile cell wall that bursts, killing the bacterium. No harm comes to the human host because penicillin does not inhibit any biochemical process that goes on within us.

Bacteria can also be selectively eradicated by targeting their metabolic pathways. Sulfonamides, such as sulfamethoxazole, are similar in structure to para-aminobenzoic acid, a compound critical for synthesis of folic acid. All cells require folic acid and it can diffuse easily into human cells. But the vitamin cannot enter bacterial cells and thus bacteria must make their own. The sulfa drugs such as sulfonamides inhibit a critical enzyme--dihydropteroate synthase--in this process. Once the process is stopped, the bacteria can no longer grow.

Another kind of antibiotic--tetracycline--also inhibits bacterial growth by stopping protein synthesis. Both bacteria and humans carry out protein synthesis on structures called ribosomes. Tetracycline can cross the membranes of bacteria and accumulate in high concentrations in the cytoplasm. Tetracycline then binds to a single site on the ribosome--the 30S (smaller) ribosomal subunit--and blocks a key RNA interaction, which shuts off the lengthening protein chain. In human cells, however, tetracycline does not accumulate in sufficient concentrations to stop protein synthesis.

Similarly, DNA replication must occur in both bacteria and human cells. The process is sufficiently different in each that antibiotics such as ciprofloxacin--a fluoroquinolone notable for its activity against the anthrax bacillus--can specifically target an enzyme called DNA gyrase in bacteria. This enzyme relaxes tightly wound chromosomal DNA, thereby allowing DNA replication to proceed. But this antibiotic does not affect the DNA gyrases of humans and thus, again, bacteria die while the host remains unharmed.

Many other compounds can kill both bacterial and human cells. It is the selective action of antibiotics against bacteria that make them useful in the treatment of infections while at the same time allowing the host to live another day.

Antibiotic resistance: How do antibiotics kill bacteria?

This is a multi-part series on antibiotic resistance in bacteria.

Eventually, we'll reach the ways in which bacteria develop antibiotic resistance, but before we get there, we'll spend a little more time on antibiotics themselves.

What have we learned so far?

1. Antibiotics are natural products, made by bacteria and some fungi. We have also learned about the difference between antibiotics and synthetic drugs. There isn't always a clear distinction since chemical groups can be added to antibiotics, making them partly synthetic and partly natural.

2. Antibiotics are a chemically diverse group of compounds. Antibiotics are not DNA. Neither are they proteins, although some antibiotics contain amino acids, which are the building blocks of proteins. In a way, antibiotics are kind of luxury molecules, since they aren't essential for life.

Bacteria don't even make them until the population reaches a certain density and phase of growth. Even though we can describe all antibiotics with a single word, there is no single description that does justice to these fascinating compounds.

We can group antibiotics into classes, either by chemical similarity - peptide antibiotics all contain amino acids held together by peptide bonds, ß-lactams all have a ß lactam ring - by the range of organisms they can kill - broad spectrum antibiotics kill a wide variety of bacteria, where narrow spectrum antibiotics have more specific targets or by the metabolic pathway that they target.

Perhaps the easiest way to categorize antibiotics is by the organisms that produce them. Even there, antibiotics defy easy groupings. The majority are made by denizens of the dirt, but both fungi and bacteria get into the act.

But what do antibiotics do?
How do they fulfill their role as agents of warfare? They do kill bacteria - but how? In a bacterial population, do all members get killed? Unfortunately, no, many antibiotics work by preventing bacterial growth. This means that most antibiotics only kill growing bacteria.

They keep bacteria from getting bigger?
No. When we talk about animals, plants, or people growing, we're really describing individual organisms getting larger. But, when we talk about bacterial growth, we're referring to the size of a bacterial population and not just the size of a cell.

In order for bacteria to grow, then, they need to make all the parts necessary for building new bacterial cells. DNA must be copied. New RNA, ribosomes, and proteins must be made. Cell walls must be built. Membranes have to be synthesized. And, then, of course the cells must divide. Many, if not most, antibiotics act by inhibiting the events necessary for bacterial growth. Some inhibit DNA replication, some, transcription, some antibiotics prevent bacteria from making proteins, some prevent the synthesis of cell walls, and so on. In general, antibiotics keep bacteria from building the parts that are needed for growth.

There are some antibiotics that act by attacking plasma membranes. Most antibiotics, though, work by holding bacterial populations in check until the immune system can take over. This also brings us, to our first mechanism of antibiotic resistance.

Persistance is resistance.

If bacteria need to grow in order to be killed by antibiotics, then bacteria, can escape from antibiotics, by NOT growing or by growing very slowly. This phenomenon has been observed with biofilms (colonies of bacteria living on a surface) (1), E. coli in urinary tract infections (2), and most notably in the slow growing bacteria, that cause tuberculosis, Mycobacterium tuberculosis, and leprosy, Mycobacterium leprae (3).

It seems funny to think that not growing can be a mechanism for survival. But if you're a bacteria, and you can hang around long enough in an inactive, non-growing state, enventually your human host will stop taking antibiotics, they will disappear from your environment and you can go back to growing.

1. P.S. Stewart 2002. "Mechanisms of antibiotic resistance in bacterial biofilms." Int J Med Microbiol. 292(2):107-13.

2. Trülzsch K, Hoffmann H, Keller C, Schubert S, Bader L, Heesemann J, Roggenkamp A. 2003. "Highly Resistant Metabolically Deficient Dwarf Mutant of Escherichia coli Is the Cause of a Chronic Urinary Tract Infection." J Clin Microbiol. 41(12): 5689-5694.

3. Gomez JE, McKinney JD. 2004. Tuberculosis (Edinb). 84(1-2):29-44.

Other articles in this series:
1. A primer on antibiotic resistance: an introduction to the question of antibiotic resistance.
2. Natural vs. synthetic drugs: what is the difference between an antibiotics and synthetic drugs?
3. How do antibiotics kill bacteria? a general discussion of the pathways where antibiotics can act and one characteristic that helps some bacteria survive.
4. Are antibiotics really only made by bacteria and fungi? It depends on what you'd like to call them.
5. The Five paths to antibiotic resistance: a quick summary

Filamentous Fungi and Filamentous Bacteria

Fungi, like bacteria, are ecologically important as decomposers as well as parasites of plants and animals. Both groups of microbes often inhabit the same ecosystem and thus compete for the same food supply. Associated with this competition is the production by both the fungi and bacteria of secondary products that function as microbial growth inhibitors or toxins. These compounds constitute a rich library of antimicrobial agents, many of which have been developed as pharmacologic antibiotics (e.g., penicillin from Penicillium chrysogenum, nystatin from Streptomyces noursei, amphotericin B from S niveus).

The superficial morphologic similarities between actinomycetes (filamentous bacteria) and molds suggest that the two groups have undergone parallel evolution. Despite the production of branching filaments and mold-like spores, the actinomycetes are clearly prokaryotes, whereas fungi are eukaryotes. Moreover, the sexual reproduction of bacteria, which typically occurs by transverse binary fission, should not be confused with asexual processes of budding and fragmentation associated with mitotic nuclear division in fungi. Most of the molds that produce septate vegetative hyphae reproduce exclusively by asexual means, giving rise to airborne propagules called conidia. On the other hand, elaborate mechanisms of sexual reproduction are also demonstrated by members of the Eumycota. Four distinct kinds of meiospores (products of karyogamy-meiosis-cytokinesis) are recognized: oospores (Oomycetes), zygospores (Zygomycetes), ascospores (Ascomycetes), and basidiospores (Basidiomycetes).

A summary of these and other diagnostic features of the fungi is presented inTable 73-1.

Table 73-1

Summary of Diagnostic Features of Fungi.


Herbal medicine
noun A herb said to kill or inhibit bacterial growth.

Mainstream medicine
(1) noun An agent obtained directly from a yeast or other organism and used against a bacterial infection.
(2) Any agent used to kill or reduce the growth of any infectious agent, including viruses, fungi and parasites.

Molecular biology
noun A substance that interferes with a particular step of cellular metabolism, causing either bactericidal or bacteriostatic inhibition sometimes restricted to those having a natural biological origin.