Elvizy’s World

Presented by Tengmi Jespa

Abstract
The treatment of bacterial infections is increasingly complicated by the ability of bacteria to develop resistance to antimicrobial agents. Antimicrobial agents are often categorized according to their principal mechanism of action. Mechanisms include interference with cell wall synthesis (e.g.-lactams and glycopeptide agents), inhibition of protein synthesis (macrolides and tetracyclines), interference with nucleic acid synthesis (fluoroquinolones and rifampin), inhibition of a metabolic pathway (trimethoprim-sulfamethoxazole), and disruption of bacterial membrane structure (polymyxins and daptomycin). Bacteria may be intrinsically resistant to _1 class of antimicrobial agents, or may acquire resistance by de novo mutation or via the acquisition of resistance genes from other organisms. Acquired resistance genes may enable a bacterium to produce enzymes that destroy the antibacterial drug, to express efflux systems that prevent the drug from reaching its intracellular target, to modify the drug’s target site, or to produce an alternative metabolic pathway that bypasses the action of the drug. Acquisition of new genetic material by antimicrobial-susceptible bacteria from resistant strains of bacteria may occur through conjugation, transformation, or transduction, with
transposons often facilitating the incorporation of the multiple resistance genes into the host’s genome or plasmids. Use of antibacterial agents creates selective pressure for the emergence of resistant strains. Here in case histories one involving Escherichia coli resistance to third-generation cephalosporins, another focusing on the emergence of vancomycin-resistant Staphylococcus aureus, and a third detailing multidrug resistance in Pseudomonas aeruginosa—are reviewed to illustrate the varied ways in which resistant bacteria develop.

INTRODUCTION

Resistance to antimicrobial agent is a recognized health problem for past years. Bacterial where known to pose a lot of problems to antibiotics due to their resistance to the drugs. Resistance to drugs by bacterial is a means developed by bacterial to survive in the milieu within which there are found. Drugs are substance that modifies the response of a tissue to it environment. They bind to receptors to elicit a biological response. Antibiotic resistant bacterial has increased as many organisms (example; Staphylococcus aureus) have developed resistance to several antibiotics; hence the search of new antibiotics is mainly due to the worrying ability of bacterial to acquire resistance to modern drugs. According to the World Head Organisation (WHO), Staphylococcus aureus is responsible for many serious community and nosocomially acquired infections, being the most frequently isolated bacterial pathogen from patients with hospital-acquired infections, especially immunocompromised patients with implants or prostheses. Asymptomatic S. aureus colonization occurs intermittently in children and adults, most commonly in the anterior nasal vestibule, but occasionally on the skin, hair, nails, axillae, perineum, and vagina. Before the introduction of antimicrobials in the 1940s, the mortality rate of S. aureus invasive infection was about 90%. The initial success of antibiotherapy was rapidly countered by the successive emergence of penicillin-resistant, then methicillin-resistant S. aureus (MRSA) strains and, since 2002, by that of vancomycin-resistant strains. The development of antibiotic resistance in S. aureus is a strong incentive that spurs vaccine development.
Antibiotics have different site of action on the bacterial cell; this implies that, bacterial develop resistance depending on the site of action of the antibiotics. Nevertheless, some bacterial are resistant to many antibiotics by different mechanism of action, and it has become very difficult to fight such bacterial.
Bacterial have developed resistance to drug by many mechanism among which is drug resistance by mutation, drug resistance by genetic transfer, drug resistance by decrease permeability ability of the drug to the membrane of the bacterial, modification of the active site of the enzyme attack by the antibiotics and finally, the over production of enzyme that inactivate the antibiotics.
The enzymes that are involved in drug resistance include; penicillinases for the penicillin antibiotics, cephalosporinase for the cephalosporin antibiotics, the beta lactamases for the beta lactam antibiotics and many others.
The fight against bacterial resistance has brought many scientists together to develop strategies to combat the situation among which is the search for new antibiotics from natural product chemistry or other means but most important is the aspect of combination therapy which has brought more light to the fight against bacterial drug resistance.

Antibiotic resistance
Antibiotic resistance is the ability of a microorganism to withstand the effects of antibiotics. It is a specific type of drug resistance. Antibiotic resistance evolves via natural selection acting upon random mutation, but it can also be engineered by applying an evolutionary stress on a population. Once such a gene is generated, bacteria can then transfer the genetic information in a horizontal fashion (between individuals) by plasmid exchange. If a bacterium carries several resistance genes, it is called multiresistant or, informally, a superbug. The term antimicrobial resistance is sometimes used to explicitly encompass organisms other than bacteria.

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 recognized soon after the natural penicillin was introduced for disease control, and bacterial strains held in culture collections from before “the antibiotic era” has also been found to harbor 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
Antibiotic resistance can also be introduced artificially into a microorganism through transformation protocols. This can aid in implanting artificial genes into the microorganism. If the resistance gene is linked with the gene to be implanted, the antibiotic can be used to kill off organisms that lack the new gene.
Why is resistance a concern?
There are a number of reasons why bacterial resistance should be a concern for physicians. First, resistant bacteria, particularly staphylococci, enterococci, Klebsiella pneumoniae, and Pseudomonas spp, are becoming common placein healthcare institutions. Bacterial resistance often results in treatment failure, which can have serious consequences, especially in critically ill patients. Inadequate empiric antibacterial therapy, defined as the initial use of an antibacterial agent to which the causative pathogen was not susceptible, has been associated with increased mortality rates in patients with bloodstream infections due to resistant Pseudomonas aeruginosa, Staphylococcus aureus, K pneumoniae, Escherichia coli, Enterobacter spp, coagulase-negative staphylococci, and enterococci. Prolonged therapy with antimicrobial agents, such as vancomycin or linezolid, may also lead to the development of low-level resistance that compromises therapy, but that may not be detected by routine susceptibility testing methods used in hospital laboratories.
Resistant bacteria may also spread and become broader infection-control problems, not only within healthcare institutions, but in communities as well. Clinically important bacteria, such as methicillin-resistant S aureus (MRSA) and extended-spectrum lactamase (ESBL) producing E coli, are increasingly observed in the community. Infected individuals, including children, often lack identifiable risk factors for MRSA, and appear to have acquired their infections in a variety of community settings. Community- associated MRSA strains are typically less resistant to antimicrobial agents than healthcare-associated MRSA, but are more likely to produce toxins, such as Panton–Valentine leukocidin. The spread of resistant bacteria within the community poses obvious additional problems for infection control, not just in long-term care facilities but also among sport teams, military recruits, and even children attending day care centers a task that is complicated by the increased mobility of our population. Finally, with respect to the cost-containment pressures of today’s healthcare environment, antibacterial drug resistance places an added burden on healthcare costs, although its full economic impact remains to be determined.
Causes and risk factors
Antibiotic resistance can be a result of horizontal gene transfer and also of unlinked point mutations in the pathogen genome and a rate of about 1 in 108 per chromosomal replication. The antibiotic action against the pathogen can be seen as an environmental pressure; those bacteria which have a mutation allowing them to survive will live on to reproduce. They will then pass this trait to their offspring, which will result in a fully resistant colony.
Several studies have demonstrated that patterns of antibiotic usage greatly affect the number of resistant organisms which develop. Overuse of broad-spectrum antibiotics, such as second- and third-generation cephalosporin, greatly hastens the development of methicillin resistance. Other factors contributing towards resistance include incorrect diagnosis, unnecessary prescriptions, improper use of antibiotics by patients, the impregnation of household items and children’s toys with low levels of antibiotics, and the administration of antibiotics by mouth in livestock for growth promotion.
Researchers have recently demonstrated the bacterial protein LexA may play a key role in the acquisition of bacterial mutations.

ORIGIN OF DRUG RESISTANCE
Human inability to respect the complete medication period given to them has mark a rapid increase in drug resistance by bacterial. When incomplete medication is carried out by a patient, it makes the bacterial to develop resistance against that drug, because the bacterial will develop new ways (factors) to prevent the conditions it is exposed to. By doing so, the bacterial cell wall may become impermeable to the drug, or produce enzymes that deactivate the drug and many others. So it is convenient to always take the complete medication given. Bacterial have become resistant to many drugs by developing certain factors which are explicitly given as follows;
Drug resistance by mutation:
Bacterial have the ability to multiply very rapidly, such rapid multiplication also pose a chance to the bacterial to undergo mutation which will render the bacterial cell resistance to a particular drug. The mutation can be the change in the bacterial structure, or the enzymes attacked by the drug changes it’s structure or composition. This works in line with the fact that patients do not always complete the course of their antibiotic treatment given that the symptoms of their illness have disappeared. To elaborate, the drug becomes foreign to its target due to mutation at the drug target.
Drug resistance by genetic transfer:
Genetic materials can be transferred from one bacterial cell to another by transduction or by conjugation. This therefore means that bacterial are capable of exchanging genetic materials and hence, a resistant bacterial cell can transfer the gene responsible for its resistance to a drug to a non resistant bacterial cell and this therefore cause the latter to be resistant to the same antibiotics.
In transduction, plasmids which are small segment of genetic information of a bacterial are transferred by means of bacterial viruses or bacteriophage. If the plasmid which contains the gene for resistance to a particular antibiotic agent leaves a resistant bacterial cell to a non resistant bacterial cell, then it will cause the latter to acquire resistance to that antibiotic. For example, the genetic information required to synthesize beta- lactamase can be pass on in this way and hence rendering bacterial resistance to beta- lactam antibiotic agent.
Conjugation is a method used mainly by Gram negative rod-shaped bacterial; it involves two bacterial cells building a sex bridge through which genetic information can pass. Hence, the bacterial cell passes genetic information directly to each other.
Change in permeability to bacterial cell:
Bacterial can undergo mutation which causes a decrease in permeability of the drug to the bacterial cell. Hence, causing the bacterial to be non susceptible to the attack of the drug. The mutation can be due to the change in polarity of the cell wall or cell membrane of the bacterial which repels the drug. The bacterial might develop a new protective coat which is impermeable to the drug. Many bacterial have developed resistance through this means.

Drug resistance by the production of drug deactivating enzymes:
Bacterial can produce enzymes that deactivate the antibiotics. These enzymes deactivate antibiotics by modifying them to inactive compounds.
Some of the enzymes produced by the bacterial include; penicillinase, cephalosporinase, beta- lactamase and much more. As an example, the beta- lactamases deactivates beta- lactam antibiotics by breaking the beta- lactam ring essential for activity.
Antibiotic usage in agriculture: creates 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:

Antibiotic resistance in genetically modified crops
A further source of concern is the widespread use of antibiotic-resistance genes as “markers” in genetically modified crops. Most of the companies insert antibiotic-resistance genes as “markers” during the early stages of developing their Genetically Modified( GM corps). This enables the scientists to detect when the genes that they are most interested in (herbicide-resistant genes or insecticidal toxin genes) have been inserted into the crop. The antibiotic-resistance genes then have no further role to play, but they are not removed from the final product. This practice has met with criticism because of the potential that the antibiotic-resistance genes could be acquired by microorganisms. In some cases these marker genes confer resistance to “front line” antibiotics such as the beta-lactams
Looking at penicillin, some bacterial develop resistance by producing enzymes called; amidases which slits off the R-side chain from the amino group of the 6-aminopenicilanic acid (6-APA). Also, metabolically inactive organisms are phenotypically resistant to penicillin but genotypically fully susceptible to penicillin. Such organism can act as “persisters” both in vitro and in vivo.
CASE STUDIES

E coli: Development of Resistance to Third-
Generation to penicillin

E coli is a common cause of urinary tract infections and bacteremia in humans, and is frequently resistant to aminopenicillin, such as amoxicillin or ampicillin, and narrow spectrum cephalosporins. Resistance is typically mediated by the acquisition of plasmid beta- lactamases which hydrolyze and inactivate these drugs. Some E coli strains develop resistance to third-generation cephalosporins and monobactams (aztreonam) commonly arising through mutation of the enzymes. Resistance to cephamycins and other lactams such as amoxicillin may arise as a result of changes in the porins in the outer membrane (proteins that form the water-filled channels through which drugs and other molecules enter the bacterial cell). Such changes decrease or eliminate the flow of small hydrophilic molecules like lactam drugs across the membrane. The following case illustrates the interaction of these mechanisms of resistance. A 4-year-old girl was admitted to an
Urban hospital in Atlanta with a plastic anemia and bacteremia. Blood cultures collected during her first week in the hospital were positive with E coli isolates that were resistant to ampicillin and narrow-spectrum cephalosporins but remained susceptible to third-generation cephalosporins. Over the next 3 weeks, the child received a variety of antimicrobial agents directed against E coli and other suspected bacterial pathogens in an attempt to treat her persistent fevers and bacteremia. The antibacterial agents included penicillins (ticarcillin, oxacillin, and mezlocillin), aminoglycosides (gentamicin), and third-generation cephalosporins.

ACTION OF PENICILLIN
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 recognized 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.

Structure A showing Fleming’s slide

Structure of penicillin
Penicillin is a bicyclic compound consisting of a four membered beta- lactam ring fused to a five membered thiazoridine ring. The skeleton of the molecule reveal that it is derived from the amino acid valine and cysteine. The acyl side chain “R” varies depending on the make up of the fermentation as shown below;

Structure Activity Relationship

From the synthesis of great analogs of penicillin studies, reveals the following conclusion about the activity of the structure of penicillin;
• The strain beta lactam ring most be present
• The free carboxylic acid at position three is essential
• The bicyclic system is important because it confers strain of the beta lactam ring, the greater the strain the greater the activity and also the greater the instability of the molecule to other factors.
• The stereochemistry of the bicyclic ring
With respect to the acyl amino side chain is essential for activity.
From all the above observations, it is clear that very little variations can be done on the structure of the penicillin molecule. One of the penicillin analogs is penicillin G for which “R” is a benzyl group, as it is shown below;

Penicillin G

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
BRIEF PROPERTIES OF PENICILLIN G
The two natural penicillins obtained from culture filtrates of Penicillium notatum or the closely related species P. chrysogenum are penicillin G and the more acid-resistant penicillin V. They are active only against Gram-positive bacteria (which have a thick layer of peptidoglycan in the wall) and not against Gram-negative species, including many serious pathogens like Mycobacterium tuberculosis (the cause of tuberculosis). Nevertheless, the natural penicillins were extremely valuable for treating wound pathogens such as Staphylococcus in wartime Europe.
An expanded role for the penicillin came from the discovery that natural penicillin can be modified chemically by removing the acyl group to leave 6-aminopenicillanic acid and then adding acyl groups that confer new properties. This modern semi-synthetic penicillin such as Ampicillin, Carbenicillin and Oxacillin has 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 bacterial.
Although the penicillin 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.

ACID SENSITIVITY OF PENICILLIN
Penicillin is recognized to be acid sensitive in the stomach and this has made them to be inactive orally. There are three reasons which account for the acid sensitivity of penicillin.
Ring strain:
The bicyclic system of the penicillin molecule consists of a four membered ring and a five membered ring. As a result, penicillin suffers large angle torsional strain. Acid catalyzed ring opening relieved this strain by breaking open the high strain four membered ring.
A highly reactive beta- lactam carbonyl group:
The carbonyl group in the beta- lactam ring is highly susceptible to nucleophiles and as such does not behave as a normal tertiary amide which is usually quite resistant to nucleophlic attacks. This difference in reactivity is due to the fact that stabilization of the carbonyl is possible in the tertiary amide but impossible in the beta- lactam ring. The beta- lactam nitrogen is unable to feed its lone pair of electron into the carbonyl group since this would require the bicyclic ring to adopt an impossible strain plat system. As a result, the lone pair of electron is delocalized on the nitrogen atom and the carbonyl group is far more electrophilic than expected for a normal tertiary amine. A normal tertiary amine is far less susceptible to nucleophiles since resonance structure reduces the electrophilic character of the carbonyl group.
Influence of the acyl side chain:
The neighboring acyl group can actively participate in the mechanism of the beta- lactam ring opening by attacking the carbonyl group of the beta- lactam ring, hence it is self destructive.
Tackling the problem of acid sensitivity
It is then very necessary to solve the problem of acid sensitivity of penicillin. From the above factors, nothing can be done about the problem of ring strain and the problem of the highly reactive beta- lactam carbonyl. In this view, only the third factor can be solved by reducing the neighboring participation of the acyl amino side chain, which is to make it difficult if not impossible for the acyl amino side chain carbonyl group to attack the beta- lactam carbonyl which will lead to the breaking of the beta- lactam ring. This point is solved by introducing an electron withdrawing group to the carbonyl carbon of the acyl amino side chain. By inductive pulling effect, the electron withdrawing group pulls electrons from the carbonyl oxygen and reduces its tendency to act as a nucleophile. An example is penicillin V (pen V).
How penicillin is destroyed by beta- lactamase
Bacterial develop resistance to penicillin by secreting an enzyme (beta- lactamase) that hydrolysis penicillin before it can interfere with bacterial cell wall synthesis. Beta- lactamase destroy penicillin by breaking the beta- lactam ring which is necessary for the activity of penicillin.
Mechanism of action of penicillin.
Penicillin is a beta lactam anti biotic was inhibits bacterial cell wall synthesis.
In contrast to animal cells, bacterial posses a rigid outer layer, the cell wall which “corsets” the bacterial cell, which posses an unusually high internal osmotic pressure. Injury in the cell wall or inhibition of it formation can lead to lyses of the cell. In hypertonic environment, damaged cell wall, leads to formation of spherical bacterial “protoplast” limited by the fragile cytoplasmic membrane. In the environment of ordinary tonicity, the protoplast explodes, and the cell dies, meaning penicillin is bactericidal.
Beta-lactam antibiotics work by inhibiting the formation of peptidoglycan cross-links in the bacterial cell wall. The β-lactam moiety (functional group) of penicillin binds to the enzyme (DD-transpeptidase) that links the peptidoglycan molecules in bacteria, which weakens the cell wall of the bacterium (in other words, the antibiotic causes cytolysis or death due to osmotic pressure). In addition, the build-up of peptidoglycan precursors triggers the activation of bacterial cell wall hydrolysis and autolysins, which further digest the bacteria’s existing peptidoglycan.
Gram-positive bacteria are called protoplasts when they lose their cell wall. Gram-negative bacteria do not lose their cell wall completely and are called spheroplasts after treatment with penicillin.
Penicillin shows a synergistic effect with aminoglycosides, since the inhibition of peptidoglycan synthesis allows aminoglycosides to penetrate the bacterial cell wall more easily, allowing its disruption of bacterial protein synthesis within the cell. This results in a lowered Minimum Bactericidal Concentration (MBC ) for susceptible organisms.
SIDE EFFECTS
Common adverse drug reactions (≥1% of patients) associated with use of the penicillins include diarrhea, hypersensitivity, nausea, rash, neurotoxicity urticaria, and/or super infection (including candidiasis). Infrequent adverse effects (0.1–1% of patients) include fever, vomiting, erythema, dermatitis, angioedema, seizures (especially in epileptics), and/or pseudo membranous colitis.
Pain and inflammation at the injection site is also common for parenterally administered benzathine benzylpenicillin, benzylpenicillin, and, to a lesser extent, procaine benzylpenicillin.
Although penicillin is still the most commonly reported allergy, less than 20% of all patients who believe that they have a penicillin allergy are truly allergic to penicillin; nevertheless, penicillin is still the most common cause of severe allergic drug reactions.
Allergic reactions to any β-lactam antibiotic may occur in up to 10% of patients receiving that agent. Anaphylaxis will occur in approximately 0.01% of patients. It has previously been accepted that there was up to a 10% cross-sensitivity between penicillin-derivatives, cephalosporins, and carbapenems, due to the sharing of the β-lactam ring. However recent assessments have shown no increased risk for cross-allergy for 2nd generation or later cephalosporins. Recent papers have shown that a major feature in determining immunological reactions is the similarity of the side chain of first generation cephalosporins to penicillins, rather than the β-lactam structure that they share.
Fighting penicillin drug resistance
Chemist have developed new methods of fighting penicillin drug resistance, among this methods is;
• The development of drugs that inhibit beta-lactamases, an example is clavolanic acid, if such a drug is given alon side with penicillin, the antibiotics is not destroyed. This is an example of a prodrug that has no therapeutic effect but acts by protecting a therapeutic drug. A sulfone is also a beta-lactamase inhibitor which is obtained by oxidizing the penicillin sulfur atom with a peroxyacid.
• Another means of fighting resistance is by developing new targets.

CONCLUSION

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