What makes penicillin resistant

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Register to receive updates. Visit the source of this article and learn more! Exploring Everyday Chemistry Join this course for free! Before You Go! Why Not 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. Skip directly to site content Skip directly to page options Skip directly to A-Z link. Section Navigation. Facebook Twitter LinkedIn Syndicate. How Antibiotic Resistance Happens.

Minus Related Pages. On This Page. Some help us. Some make people, crops, or animals sick. Some of those germs are resistant to antibiotics.

Antibiotics kill germs that cause infections. It was this experiment performed by Heatley and colleagues that provided key data to demonstrate the effect of penicillin in vivo [ 4 , 5 ]. Eight mice were injected with a fatal dose of Group A streptococcus. After one hour, two mice were given a single dose of penicillin 10 mg and two were given 5 mg of penicillin, plus three additional doses of 5 mg at 3, 5, 7, and 11 hours after infection.

Four mice served as controls and received no penicillin. Seventeen hours after the initial infection, all mice in the control group had died, while all the mice that had received a penicillin dose survived Figure 1 A.

This remarkable observation provided the key evidence that penicillin had potential as a life-saving drug. The first mouse experiment and ceramic vessels which were used to grow the fungus. Results from the first penicillin trial experiment involving mice which was performed by the scientists at Oxford in left panel. Old-fashioned bedpan, acquired from Radcliffe Infirmary hospital in Oxford to grow the first batch of penicillin.

Ceramic culture vessel designed by Florey and colleagues to increase the yield of penicillin production right panel. Figures from [ 4 ]. The main challenge faced by Florey and his team was to produce enough penicillin for further experimentation on mice, while human trials required much larger doses.

The yield and production had to be increased, but during wartime no help was available from commercial firms because resources were so scarce. Originally, old-fashioned bedpans were used to grow Penicillium , but these did not generate sufficient yield [ 4 ].

With limited equipment, Florey and colleagues designed their own ceramic culture vessel. Heatley and Florey then arranged the vessel to be mass produced by a pottery firm about meters away from Oxford, which was suggested to him by his acquaintance in potteries Figure 1 B. In the end of , Florey and colleagues received the vessels, and Heatley inoculated them with the fungus on December 25th. By the start of February , the Oxford team had purified sufficient material for clinical trials in humans.

The first patient to receive the penicillin as part of the toxicity test was a woman with terminal cancer. Shortly after she was given penicillin by injection, she developed fever and rigor, which were caused by impurities of pyrogenic origin that were contained in the penicillin mix [ 5 ]. The second patient to receive a purified dose of penicillin was a policeman at the Radcliffe Infirmary who had severe staphylococcal and streptococcal infection [ 5 ].

Repeated intravenous injections of penicillin over 5 days had a profound effect on his recovery. Eventually, the overall shortage of penicillin forced the treatment to be terminated, and the patient relapsed and died shortly after [ 6 ]. Florey, Heatley, and Chain conducted a series of further clinical trials between to which involved patients. The results demonstrated a remarkable effect of penicillin in combating bacterial infections without any toxic side effects [ 7 ].

The Oxford Team immediately recognized the potential of penicillin for treatment of injured soldiers and wounded civilians during the war. However, the funding and the capacity for mass production of penicillin were not available in the United Kingdom, so in Florey and Heatley went to the United States, which was not yet at war, to seek support.

The work of the project had three main streams: the first was focused on improving the purification of penicillin; the second aimed to find more potent strains of Penicillium , and Heatley worked closely with the US Department of Agriculture to characterize these strains; the last stream, headed by Florey and his American partners, was focused on finding pharmaceutical companies which would take on mass production of penicillin.

Eventually, 15 drug companies in both the U. The first trials of penicillin in the war setting were conducted by Florey in the military hospitals in north Africa in , and showed that penicillin was effective when used on both fresh and infected wounds [ 8 ].

It was evident that penicillin would be instrumental in the war effort to save the lives of many soldiers. Soon, collaborative efforts between the government, industry, and British and American scientists led to sufficient supplies of penicillin being manufactured by D-Day in , when Allied troops landed in France [ 8 , 9 ]. After the war, by , penicillin was widely available for prescription. Chain and Abraham had continued to work on the structure of penicillin until , when Abraham first proposed the beta-lactam structure.

The discovery of penicillin changed the course of history. Penicillin saved thousands of wounded soldiers and civilians during the biggest of the wars, and its discovery laid the foundations of the antibiotic era and subsequent development of other more potent antibiotics. An essential structural element for most bacteria is the cell wall, a protective layer of peptidoglycan PGN whose main function is to preserve cell integrity and shape and prevent macromolecules from penetrating into the cell [ 13 ].

PGN is located just outside the cytoplasmic membrane, and is composed of chains of alternating N -acetylglucosamine Glc N Ac and N -acetylmuramic acid Mur N Ac residues, which are covalently crosslinked via short peptides Figure 2. During growth and division, PGN is continuously synthesized and remodeled.

Therefore, it is essential for bacteria to be able to synthesize the components of PGN and assemble them into a single macromolecule. The characteristic strength of PGN resides in its net-like conformation that is mainly derived from peptide cross-linkages [ 13 ].

These linkages are formed by the activity of specific enzymes called transpeptidases or Penicillin-Binding Proteins PBPs. Penicillin, like other components of the beta-lactam antibiotics, contains a four-membered beta-lactam ring Figure 3 , which is responsible for the inhibition of transpeptidase [ 14 ].

By mimicking the last two D-alanine residues of the peptide, penicillin is able to bind irreversibly the active site of the transpeptidase, preventing the enzyme from cross-linking the peptidoglycan strands. Therefore, by blocking the formation of peptide bridges, penicillin prevents new PGN formation and the cell is susceptible to lysis, as the PGN is no longer able to provide resistance against osmotic stress.

Furthermore, penicillin specifically targets bacteria, as eukaryotic cells lack both PGN and the enzymes responsible for PGN synthesis. Schematic representation of the mechanism of penicillin action. PGN is composed of polysaccharide chains made of Glc N Ac and Mur N Ac units shown in different shades of blue which in turn have small peptides attached to them.

The transpeptidase enzyme PBP in brown catalyzes the formation of cross-linkages between these peptides, by specifically binding the last two D-alanine residues of one peptide red circles. Penicillin mimics the structure of these residues and inactivates the PBP by forming an irreversible covalent bond to the catalytic serine residue of the enzyme [ 69 ]. Chemical structures of different classes of penicillins.

Examples of different generations of penicillins are shown. Beta-lactam ring, the common feature of all classes, is highlighted in brown and the corresponding chemical substitute on the side chain is color-coded: blue, penicillin G benzylpenicillin class, 1st generation ; yellow, methicillin 2nd generation ; green, ampicillin aminopenicillin class, 3rd generation ; orange, carbenicillin carboxypenicillin class, 4th generation ; purple, azlocillin ureidopenicillin class, 4th generation.

The classification of penicillins relies on chemical substitutions on the residue attached to the beta-lactam ring, which confer different activities. Benzylpenicillins, for example, are more active against Gram-positive bacteria in particular cocci, such as staphylococci, pneumococci, and other streptococci, and bacilli, including Bacillus anthracis, Clostridium perfringens , and Corynebacterium diphtheriae , but less efficacious against Gram-negative bacteria.

The inability to act against Gram-negative bacteria is observed not only among benzylpenicillins but also across many different antibiotics. This is largely due to two factors: firstly, unlike Gram positive bacteria, Gram negative species contain the outer membrane, which acts as a selective barrier, blocking the penetration of penicillin [ 15 ]; secondly, some Gram-negative bacteria have acquired specific genes which encode for penicillinases also known as beta-lactamases , a class of enzymes that inactivate penicillin by hydrolysis of the beta-lactam ring [ 16 ].

This shifted pharmacological research towards the development of semisynthetic, beta-lactamase-resistant penicillins i. The relatively narrow spectrum of activity of these antibiotics and the need for broader coverage against Gram-negative organisms, served as an incentive to expand the second generation penicillins.

In the s, the third generation and broad-spectrum penicillins also known as aminopenicillins, were introduced. Amoxicillin and ampicillin are the main examples of this group and unlike their predecessors, third generation penicillins proved to be more effective against a wider group of Gram-negative bacteria including Haemophilus influenzae , Escherichia coli , Salmonella spp.

The last generation of penicillins which includes carboxypenicillins and ureidopenicillins further broadened the spectrum of penicillin coverage against Gram-negative bacteria and displayed potent activity against Pseudomonas aeruginosa [ 17 ]. In addition to penicillins, other classes of beta-lactam compounds were discovered and have been introduced for clinical use. In , the first component of the cephalosporin family was isolated from the fungus Cephalosporium acremonium [ 18 ].

Several generations of this novel antibiotic have been developed through different chemical modifications of the natural compound originally isolated, increasing the spectrum of their activity. Since the late s, both new discoveries and advances in chemical alterations of the basic beta-lactam structure allowed production of more beta-lactam antibiotics, including the penems, carbapenems, and monobactams [ 19 ].

The first sign of antibiotic resistance became apparent soon after the discovery of penicillin. In , Abraham and Chain reported that an E. The spread of penicillin resistance was already documented by , when four Staphylococcus aureus strains were found to resist the action of penicillin in hospitalized patients [ 21 ].

During the next few years, the proportion of infections caused by penicillin-resistant S. By the late s, more than 80 percent of both community and hospital-acquired strains of S. The rapid spread of penicillin resistance temporarily came to a halt after the introduction of the second-generation, semisynthetic methicillin in the s.

However, methicillin-resistant strains soon emerged, and only in was this mechanism of resistance unraveled [ 23 ]: these strains harbored an altered PBP, designated PBP-2a, which showed a reduced affinity for penicillin, thereby conferring resistance to penicillin. PBP-2a is encoded by mecA , a gene located on the S. In approximately 20 years, methicillin resistance became endemic in the U.

In , strains of S. By , the percentage of cases associated with antibiotic-resistant pneumococcus had tripled compared to , reaching In , beta lactamase-producing gonococci were isolated in England and the U. Rapid spread of gonococcus resistance followed [ 33 ] and in the year period after the first introduction of penicillin to treat gonorrhea, the prevalence of gonococcal penicillin-resistant strains reached its peak, particularly in Asia [ 30 ].

Furthermore, in , a large outbreak of resistant non-beta-lactamase producing gonococcus affected Durham city in North Carolina U. Many medical advances are dependent on the ability to fight infections using antibiotics, including joint replacements, organ transplants, cancer therapy, and treatment of chronic diseases like diabetes, asthma, and rheumatoid arthritis.

Penicillin, the first commercialized antibiotic, was discovered in by Alexander Fleming. Ever since, there has been discovery and acknowledgement of resistance alongside the discovery of new antibiotics. In fact, germs will always look for ways to survive and resist new drugs. More and more, germs are sharing their resistance with one another, making it harder for us to keep up.

Find more information on the development of antibiotic resistance in the latest AR Threats Report. Skip directly to site content Skip directly to page options Skip directly to A-Z link.