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Antibiotic resistance mechanisms in bacteria

Antibiotics-Antibiotic resistance mechanisms in bacteria

What is antibiotic resistance??

Antibiotics are medicines or drugs that are used to treat bacterial infections by destroying the bacteria or keeping their multiplication on a check. ?

Antibiotic resistance?is the ability of the bacteria to withstand the effects of antibiotics?causing?the bacteria to become?antibiotic-resistant.??

Infections by antibiotic-resistant bacteria are difficult to treat than those caused by non-resistant bacteria. Antibiotic resistance can induce higher medical costs, prolonged hospital stays, and increased mortality.?

Bacteria incorporate a diverse array of sophisticated mechanisms for?self-defense?against antibiotics. Very often multiple mechanisms are accommodated simultaneously to assure their absolute safety from the antibiotics.?

Antibiotic resistance mechanism?

When we are under attack, mostly we use two strategies to save ourselves ? Offensive strategy and defensive strategy.??

An offensive strategy must be?counterattack?or destroy the weapon of the attacker while the defensive mode is mostly saving yourself by hiding.?

In the marketing industry, the offensive strategy includes attacking the market by targeting the weaknesses of the competitor and emphasizing the company’s strengths in comparison. A defensive strategy aims to counter the product claims made by the competitor or highlights the effectiveness of its products within the wake of competitor claims.?

Bacteria would adopt both the offensive and defensive strategies to combat.?

    1. Offensive strategy ? Stop or destroy the antibiotics?
    2. Defensive strategy – Modify or bypass the target

Antibiotic resistance mechanisms in bacteria

Offensive strategy

Bacteria work to stop the antibiotics reach their target (specific sites or receptors on or inside the bacteria) at a high concentration to protect themselves from the detrimental effects of the antibiotics.?

Some of the several mechanisms to accomplish this strategy are

  1. Antibiotic modification

The most common mechanism to make an antibiotic ineffective is by modifying the antibiotics, especially for antibiotic classes such as aminoglycosides, chloramphenicol.?

Bacteria produce certain enzymes that?can modify?the antibiotics by adding different chemical groups. This could lead to the inability of the modified antibiotic to bind its target.?

Aminoglycosides?

The aminoglycosides are bactericidal antibiotics (kill bacteria directly) with broad-spectrum of activity (effective against a broad range of bacteria). Examples of aminoglycoside antibiotics are gentamycin, kanamycin, streptomycin, etc.?

Many?aminoglycoside modification?enzymes (AMEs), capable of modifying the aminoglycoside antibiotic exist in aminoglycoside antibiotic producer bacteria as a means of self-resistance.?

For example, the antibiotic streptomycin is produced by the bacteria?Streptomyces griseus. This bacterium produces an enzyme called streptomycin-6 phosphotransferase that converts?antibiotic?streptomycin to an inactive precursor streptomycin-6-phosphate.?

The antibiotic-producing bacteria accomplish self-resistance by maintaining an association between the synthesis of antibiotics and the role of modification enzymes.?

However, it is important to note that, some species of bacteria might not produce antibiotics but still contain modification enzymes and vice versa.?

  1. Antibiotic degradation

Some bacterial enzymes?can destroy?the active component of the antibiotic and thereby rendering the antibiotic ineffective.?

Beta (?)-lactam antibiotics?

?-lactam antibiotics inhibit the cell wall synthesis in the bacteria. ?-lactam antibiotics?are the most widely used class of antibiotics. Examples are penicillin, cephalosporins, monobactams, etc.?

Resistance to???-lactam antibiotics is normally granted by antibiotichydrolyzing?enzymes?(hydrolytic?enzymes?enable?the?breaking?of bonds in molecules with the addition of the elements of water)?known as???-lactamases.?

  1. Pump out the antibiotic

Another commonly used mechanism for self-resistance by the bacteria is the efflux of antibiotics.??

There are efflux pumps located on the bacterial cell wall that is proficient to efflux certain materials or waste out of the bacterial cell.???

Pumps located on the bacterial cell wall - antibiotic resistance mechanisms in bacteria
Image credit Canva

Bacteria can deliberately manipulate these pumps to efflux out the incoming antibiotics.?

However, the efflux of antibiotics usually occurs in conjunction with other mechanisms, such as modification of the antibiotic or target.?

Anthracyclines?

Anthracyclines are extracted from Streptomyces bacterium, usually used for the treatment of cancer.?

For example,?Daunoxilacin?(Dnr) and doxorubicin (Dox) are?anthracyclins?produced by?Streptomyces?peucetius. These two antibiotics intercalate with DNA preventing further rounds of replication.?

Efflux of these antibiotics in?S.?peucetius?occurs by?an efflux pump,?ABC (ATP Binding Cassette) family transporter?DrrAB.?

Bacteria can also undergo mutations and can produce more of these pumps.?

  1. Decreasing the membrane?permeability???

The membranes on the bacterial cell wall are permeable to take up the nutrients around them, through which antibiotics also gets inside the bacterial cell.?

Bacteria can decrease the permeability of the cell wall and thereby decreasing the concentration of the antibiotics gets inside of it.?

  1. Antibiotic sequestration

There are certain drug-binding proteins present in the bacteria, capable of preventing the antibiotic from reaching its target.?

Bleomycin?

Bleomycin is classified as an “antitumor antibiotic.” The primary mechanism of bleomycin resistance in the producers of the bleomycin family of antibiotics consists of sequestration of antibiotics by binding proteins.?

Defensive strategies?

Some of the several mechanisms to accomplish this strategy are?

  1. Target modification

Bacteria can make alterations in the composition or structure of the target (which is a specific receptor or?sites) in?the bacteria thereby inhibiting the antibiotic from interacting with the target.??

Alternatively, bacteria could add different chemical groups to the target structure, thereby shielding it from the antibiotic.?

This type of target modification is employed in self-resistance against several classes of antibiotics, including???-lactams,?glycopeptides, macrolides,?lincosamides,?and aminoglycosides.?

Glycopeptide?antibiotics such as vancomycin and?tricoplanin?inhibit cell wall?transpeptidation?(transfer of one or more amino acids from one peptide chain to another)?and?transglycosylation?(transfer of a sugar residue from one glycoside to another)?by associating with peptidoglycan precursors in the bacteria.?As a resistance mechanism, bacteria can make a change in the peptidoglycan precursor to achieve antibiotic resistance.??

  1. Expression of alternative?proteins

Some bacteria can produce alternative proteins that can be used instead of the ones that are inhibited by the antibiotic.?

Examples??

Synthesis of the additional B subunit of DNA gyrase for novobiocin resistance?

Synthesis of alternate resistant RNA polymerase for rifamycin resistance??

  1. Target bypass

Sometimes bacteria can produce a different variant of a structure it needs or bypasses the original target by producing additional low-affinity targets.??

Antibiotic resistance transfer mechanism in the bacteria

Intrinsic resistance?

Almost all the antibiotic molecules are naturally produced by microorganisms.? Bacteria that produce antibiotics should also?possess?self-resistance mechanisms against their antibiotics.??

The co-existence of antibiotic producer and non-producer bacteria resulted in the co-evolution of resistance mechanisms in non-producing environmental bacteria to overcome the action of antibiotics produced by the producer bacteria.?

These bacteria are often reviewed to be ?intrinsically? resistant to one or more antibiotics. Therefore, antibiotic resistance?is?ancient,?and it is the expected result of the interaction of many organisms with their environment.?

The intrinsic antibiotic resistance mechanisms are fastened in the core genetic make-up of the bacteria.?

It is normally chromosome encoded and includes non-specific efflux pumps (emerged as a general response to environmental toxins), antibiotic inactivating enzymes, or mechanisms that serve as permeability barriers.?

As, the intrinsic resistant mechanism in?E.?coli?includes a broad substrate-specific efflux pump that can export different classes of antibiotics, dyes, detergents.??

Bacteria bearing intrinsic mechanisms of resistance are not of much concern. The real problem is with acquired resistance.??

Acquired resistance?

The acquired antibiotic resistance poses a serious threat to human health. In acquired resistant mechanisms, the context of the resistant determinants is shifted from chromosomal to plasmid-mediated?(plasmids are circular, double-stranded extrachromosomal DNA molecule that can replicate independently)?leading to enhanced expression and dissemination.??

This includes plasmid-encoded specific efflux pumps and enzymes that can modify the antibiotic or the target of the antibiotic.?

The acquired resistance mechanisms are commonly obtained by Horizontal gene transfer (HGT).??

Horizontal gene transfer?

Horizontal gene transfer is a process in which bacteria can share genes. Horizontal gene transfer can occur both between the bacteria of the same species and between different species. There are several different mechanisms by which horizontal gene transfer occurs in the right conditions.?

Transfer of antibiotic-resistant determinants between bacterial populations by horizontal gene transfer involves??

  1. Transformation with free DNA
  2. Transduction by bacteriophages
  3. Conjugation involving plasmids

All three HGT mechanisms are widely employed in nature though certain species of bacteria prefer one mechanism more heavily over the others.?

For example, Streptococci participate more effectively in transformation whereas?enterobacteria?commonly use conjugation plasmids for the exchange of genetic information.??

1.Transformation?

Transformation is the process by which?bacteria?can alter the genetic material by direct uptake of?exogenous genetic material (foreign DNA)?and incorporating it from its surroundings through the cell membrane.?

Any gene can be transferred this way and therefore some foreign DNA can be harmful to bacteria and there are mechanisms by which bacteria can degrade this incoming DNA.?

Transformed bacterial colonies on a petri plate - transformation is used a antibiotic resistance tranfer mechanism in bacteria
Image credit Canva

However, if bacteria pick up the antibiotic resistance gene and are subsequently exposed to that antibiotic this bacterium will be better off than susceptible?neighbors?and increase in number.?

Therefore, if the incoming DNA is beneficial, it incorporates and provides a benefit by maintaining it.??

Transformation is best characterized in Gram-positive bacteria?Streptococcus pneumonia?and?Bacillus subtilis.?

Transformation seems to have played an important role in the evolution of antibiotic-resistant strains of?Streptococcus and Neisseria.?

2.Transduction?

Transduction is the process by which an exogenous genetic material (foreign DNA) is introduced into a bacterial cell by a bacteriophage.?

Bacteriophages are viruses that attack or infect bacteria. Bacteriophage brings along genes that they picked up during infection of one bacterium. These genes may be incorporated into the DNA of the new bacterial host.??

Bacteriophages infecting a bacterial cell - transduction is used as one of the antibiotic resistance mechanisms in bacteria
Image credit Canva

Transduction is considered to have a major role in the evolution of antibiotic resistance in?Staphylococcus?aeurus, although it has been shown to occur in many bacteria at a low frequency.?

However, certain environments are believed to be hot spots for genetic exchange, for instance, sewage and wastewater treatment plants, hospital effluents, aquaculture, agricultural and slaughterhouse waste as these are prime locations for genetic exchange because of the high density of bacteria,?phages, and plasmids in these locations.?

3.Conjugation?

Conjugation is a process in which two bacteria can pair up and connect through structures in the cell membrane causing the transfer of DNA from one cell to another.?

plasmid DNA - plasmid-mediated conjugation is one of the antibiotic resistance transfer mechanisms used by the bacteria
Image credit Canva

Plasmid-mediated conjugation?as a gene transfer mechanism is, considered as a prevalent mechanism in transferring antibiotic resistance genes in nature than either transformation or transduction.?

By conjugation, genes can be transferred over long genetic distances to different species, genera, and even kingdom depending on the host range of the plasmids.?

Plasmids replicate autonomously and they can carry a collection of resistance genes thus simultaneously conferring resistance to several classes of antibiotics and metal ions.?

The ideal conditions for antibiotic resistance gene transfer by conjugation include high-density settings such as the human or animal gut, biofilms, hospitals, and co-infection conditions.?

?

According to the World Health Organization (WHO), antibiotic resistance is one of the most important public health threats of the 21st century.?

Antibiotic resistance hinders our progress in healthcare, food production, and ultimately life expectancy.?

Fighting antibiotic resistance is more like a war with the bacteria that are capable to rapidly adapt and survive.

Antibiotic resistance mechanisms in bacteriaAntibiotic resistance mechanisms in bacteria

 

?References

https://www.who.int/news-room/fact-sheets/detail/antibiotic-resistance

https://www.who.int/mediacentre/news/releases/2014/amr-report/en/?

Antibiotic Resistance

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