Issues of resistance of pathogens to antimicrobial agents

Antimicrobial resistance among pathogenic organisms is now a persistent problem and of tremendous public health care concern around the globe. These pathogens are able to develop mechanisms of resistance, the antimicrobial agents that were at one time the drug of choice. They continue to develop various mechanisms of resistance either by intrinsic or acquired, and have been able to transfer and accept different resistance genes, given rise to multi-drugs resistance bacteria called superbugs. This new phenomenon has caused an increase in the incidence of nosocomial infections making the treatment problematic for the health care providers. Resistance to antimicrobial agents is fast becoming a norm and is an enormous challenge worldwide.


INTRODUCTION
Antimicrobial resistance developed by pathogenic organisms is a global menace and has escalated over the years by the emergence of multi-drug resistant strains among these pathogens (Gould et al., 2010;Lister et al., 2009).Development of resistance to antimicrobial agents by pathogens is a fitness trait acquired to survive in whatever environment they find themselves (Koskella et al., 2011).This evolution trait (survival of the fittest) has accounted for the unparallel success of microbial existence in any part of the earth irrespective of the extreme conditions (Babalola et al., 2009).
Bacteria may possess intrinsic resistance that protect them from a particular antibiotic; or acquire resistance through chromosomal mutation or acquisition of genetic materials from other bacteria either through vertical or horizontal transfer of genes (Périchon et al., 2009).This has lead to some strains being called superbugs due to acquisition of resistant genes to different classes of antibiotics, making their treatment highly problematic for *Corresponding author.E-mail: olubukola.babalola@nwu.ac.za.Tel: +27183892568.Fax: +27183892134.both the clinicians and patients (Kelland, 2011).
Antimicrobial resistant infections can be acquired in health care facilities, in the community or through food supply (Bester and Essack, 2010;Calfee and Jenkins, 2008;Miller and Die, 2008).Globalization also makes possible the easy spread of these pathogenic organisms from one country to other countries (Dhanji et al., 2010).Examples of clinically important pathogens that are increasingly becoming multi-drug resistance to antibiotics in use are Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and Enterococcus faecalis.
This review article will focus on the survey of microbial resistance to antibiotics in use; examine mechanisms of action of antimicrobial agents and the mechanisms of antimicrobial resistances.Additionally, the issue of multidrug resistance that is fast becoming norms among these pathogens will be discussed.

MICRO-ORGANISMS AS CAUSATIVE AGENTS OF DISEASES
The major causes of human diseases are the micro-organisms and they (bacteria, fungi and viruses) have been the greatest burden to mankind.Throughout the history of mankind, there has been a continuous war between humans and the pathogenic organisms (Tenover, 2006).The infectious diseases caused by micro-organisms range from tonsillitis to pneumonia, osteomyelitis, cough, diarrhea, measles, acquired immune deficiency syndrome (AIDS), plague, tuberculosis, septicemia, candidiasis, malaria, influenza and many other diseases (Willey et al., 2010).Many people have lost their lives due to these infectious diseases, which at times reach epidemic rates (Gerberding, 2003;Jones et al., 2008).
For a disease to be established in a host, some factors have to be fulfilled by the disease causing organism.For example, the pathogen has to fight the defensive mechanisms of the host and overcome them before disease can become established (Harvey et al., 2007).The pathogens do this by secreting enzymes and spreading factors, for example strains of S. aureus secrete an enzyme coagulase, which aids the transformation of fibrinogen into fibrin, thus allowing the clotting of human and rabbit plasma (Todar, 2011).This creates a barrier between the pathogen and the leucocyte.Streptococci and Staphylococci produce a substance called fibrinolysin, which is similar to coagulase.Fibrin dissolves only human fibrin and not animal fibrin (Todar, 2011).
Streptococci are among the most common diseasecausing bacteria responsible for infections of the throat, middle ear, scarlet fever, rheumatic heart disease, gangrene, glomerulonephritis and tooth decay (Willey et al., 2010).Worldwide Streptococcus pneumonia causes one million fatal pneumonia infections a year in children (O'Brien et al., 2009).Streptococci have become resistant to many antibiotics for over thirty years (Phares et al., 2008;Rubinstein et al., 2011).Staphylococci, which can contribute to wound or burn infections, endocarditis, mastitis, toxic shock syndrome, osteomyelitis and other serious disorders, have developed resistance to many antibiotics (Waters et al., 2011).Infections due to S. aureus have continued to be a major source of morbidity and mortality in hospitals and hence a significant cause of concern among the physicians (Adaleti et al., 2010;DeLeo and Chambers, 2009).Enterococci contribute to some of the most common infections acquired in the hospitals (McBride et al., 2007) causing intra-abdominal abscesses, meningitis, endocarditis and infections of the urinary tract and soft tissues.Usually, infections resulting from strains resistant to many groups of antibiotics like the beta-lactams and aminoglycosides are treatable with vancomycin, chloramphenicol or other antibiotics (Jones et al., 1995).But resistance has developed to these drugs within the last two decades (Biendo et al., 2010).Enterococci have gained notoriety over the past decades as frequent causes of multiple antibiotic resistant, hospital-acquired Adegboye et al. 3469 bloodstream, urinary tract and surgical wound infections; and because of their capacity to transfer antibiotic resistance to other microbes (Arias et al., 2010).Shigellae are the major cause of diarrhea and dysentery throughout the world (Golberg, 2009).The frequency of strain's multiple resistances to ampicillin, trimethoprim-sulfonamide, streptomycin, chloramphenicol, tetracycline and even third generation cephalosporin is a cause of growing concern (Bhattacharya et al., 2011;Folster et al., 2011).Epidemic dysentery caused by these strains result in the death of most people infected due to resistance to antibiotics (Ahmed et al., 2006;Schroeder and Hilbi, 2008).Salmonellae are known to cause disease in human, animals and birds.The two major diseases caused by Salmonellae are gastroenteritis and typhoid fever.Salmonella typhii, the bacterium responsible for typhoid fever also joined the class of antibiotic resistant bacteria making treatment of the infection more problematic (Ray et al., 2006).The most common infections associated with Pseudomonades include skin infections, urinary tract infections, bronchitis, pneumonia, meningitis, otitis media, endocarditis, bacteremia, mastoiditis and corneal ulcers (Willey et al., 2010).P. aeruginosa infections are the frequent cause of morbidity and mortality in hospitalized patients (Fortaleza et al., 2011;Lanini et al., 2009).Treatment of these infections is complicated by the intrinsic and acquired resistant of the organism to many commonly used antimicrobial agents (Feliziani et al., 2010;Mandsberg et al., 2009).
Human diseases caused by Clostridia include tetanus, pseudomembranous colitis, botulism and gas gangrene.Clostridium difficile is called the hospital superbug because of its ability to resistant different types of antibiotics and is the leading cause of infectious diarrhea in hospitals worldwide (Rupnik et al., 2009).Some strains of the bacterium like E. coli 0157:H7 are the emerging cause of food borne and water borne diseases (Currie et al., 2007).Pathogenic strains of E. coli are responsible for infections such as urinary tract infection, neonatal meningitis, mastitis, haemolytic uremic syndrome, septicemia, peritonitis, and gastroenteritis (Olaniran et al., 2011).Klebsiella are human pathogens causing pneumonia, urinary tract infections, ankylosing spondylitis, septicemia and soft body infections (Sandhyarani, 2011).Klebsiella are resistant to quite a number of antibiotics including aminoglycosides, fluoroquinolones, sulfonamides and even carbapenems that used to be antibiotic of choice for serious infections (Song et al., 2009).Vibrios are important causes of diarrhea worldwide.Vibrio cholera 01 is the most important since is associated with pandemic and epidemic diarrhea in many countries (Olaniran et al., 2011).Multi-drug resistant V. cholera strains was reported making the treatment of the infection problematic especially in developing countries (Das et al., 2011).Protein cause urinary tract infections, meningitis in children, wound infections, rheumatoid arthritis, gastroenteritis, otitis media and pneumonia (Harvey et al., 2007).Apart from food poisoning, Listeria monocytogenes may cause meningitis, meningoencephalitis, septicemia or spontaneous abortion in pregnant women (Yin et al., 2011).
The last few decades have witnessed emergence of many new diseases and resurrection/re-emergence of previously eradicated diseases.For many of these diseases there is no treatment or cure and the possibility of controlling them is limited.For example, the emergence of multidrug-resistant strains of Mycobacterium tuberculosis is an increasing problem for populations and tuberculosis control programs in developed and developing countries alike.The pathogens are now found in what used to be safe zones is highly a worldwide concern (Wright et al., 2009).

MECHANISMS OF ACTION OF ANTIMICROBIAL AGENTS
Antimicrobial agents are compounds that destroy pathogenic microorganisms or inhibit their growth and are used in the treatment of diseases.Most of them are antibiotics, microbial products or their derivatives that can kill susceptible microorganisms or inhibit their growth.An effective chemotherapeutic agent must have selective toxicity.A drug with selective toxicity has a high therapeutic index and usually disrupts a structure or process unique to the pathogens and has fewer side effects (Todar, 2011).Antimicrobial agents may be grouped into two categories; cidal or static.Examples of bacteriocidal agents includes; bacitracin, ciprofloxacin, gentamicin, streptomycin, ampicillin, cephalosporins, vancomycin, carbenicillin, etc, while bacteriostatic agents include; rifampin, chloramphenicol, chydamycin, dapsone, erythromycin, tetracyclines, sulfonamides, etc. Antimicrobial agents are more effective against actively growing bacteria, than against non-growing persisters or spores.
Antimicrobial agents have diverse chemical structures and differ in their range of action (Moore and Payne, 2008).Some act on both Gram-positive and Gramnegative bacteria, and are said to have broad spectrum of action, for example, ampicillin, carbenicillin, rifampin, cephalosporins and streptomycin while some are only potent to either Gram-positive or Gram-negative bacteria and are said to be of narrow spectrum, for example, erythromycin, penicillin, polymycin B, dapsone, bacitracin and vancomycin (Todar 2011).
Antimicrobial agents injure microbes through several different mechanisms.Below are reviews of some of the major modes of action of antimicrobial agents.

Inhibition of cell-wall synthesis
Component of the cell wall provides rigid mechanical stability by virtue of its highly cross linked lattice work structure (Willey et al., 2010).Peptidoglycan is made up of polysaccharide chains containing alternating residues of N-acetylmuramic acid and N-acetylglucosamine (Todar, 2011).Peptide units cross-link extending from the N-acetylmuramic acid and during bacterial wall synthesis these linkages are caused by precursors which are catalysed by specific enzymes e.g.transpepidases, endopeptidases and carboxypeptidases.These enzymes are called penicillin binding proteins (PBPs) because they can be bound by beta-lactam antibiotics (Kashyap et al., 2011).
The cell wall, which is many layers thick in Grampositive organisms and quite thin in Gram-negative ones, protects the cell against rupture from hypotonic environments (Scheurwater and Burrows, 2011).Penicillin and certain other antibiotics prevent the synthesis of intact peptidoglycan; by irreversibly binding to and deactivating enzymes involves in cross-linkage of peptide chains, the cell-wall is greatly weakened, and the cell undergoes lysis (Drawz and Bonomo, 2010).Because penicillin targets the synthesis process, only actively growing cells are affected by these antibiotics.And, because human cell do not have peptidoglycan cell walls, penicillin has very little toxicity for host cells (Drawz and Bonomo, 2010).
Bacitracin and vancomycin interfere with the synthesis of the linear strands of peptidoglycan.Penicillin and cephalosporins prevent the final cross linkage of the peptidoglycans, which interferes with the construction of the macromolecular cell wall (Todar, 2011).Examples of other drugs that inhibit the synthesis of peptidoglycan are cycloserine, phosphomycin, isoniazid, carbapenems, cephamycins, monobactams and mersacidin.

Inhibition of protein synthesis
Protein synthesis as a common feature of all cells, whether prokaryotes or eukaryotes, it would seem an unlikely target for selective toxicity (Willey et al., 2010).One notable difference between prokaryotes and eukaryotes is the structure of their ribosomes.The difference in ribosomal structure accounts for the selective toxicity of antibiotics that affects protein synthesis (Willey et al., 2010).Among the antibiotics that interfere with protein synthesis are chloramphenicol, linezolid, erythromycin, streptomycin, clindamycin, fusidic acid and tetracyclines.These drugs discriminate between prokaryotic and eukaryotic ribosomes; hence their therapeutic index is fairly high (McKee et al., 2006).
Protein synthesis inhibitors work at different stages of prokaryotic mRNA translation into proteins, like initiation, elongation (including aminoacyl tRNA entry, proofreading, peptidyl transfer and ribosomal translocation) and termination (Kohanski et al., 2010).Rifampicin inhibits DNA-dependant RNA polymerase in bacterial cells by binding its beta-subunit, thus preventing transcription to RNA and subsequent translation to protein (Osburne et al., 2006).Tetracyclines inhibit cell growth by inhibiting translation.It binds to the 16S part of the 30S ribosomal subunit and prevents the amino-acyl tRNA from binding to the A site of the ribosome (Griffin et al., 2010).Chloramphenicol inhibits the formation of peptide bonds in the growing polypeptide chain by blocking peptidyl transfer step of elongation on the 50S ribosomal unit (Kostopoulou et al., 2011).Fusidic acids bind to elongation factor G (EF-G) and block translocation, thus preventing protein synethisis (Farrell et al., 2011).
Some antibiotics bind to the 30S or 50S ribosomal subunit.Erythromycin also reacts with 50S portion of the 70S prokaryotic ribosome.Some other antibiotics react with the 30S portion of the 70S prokaryotic ribosome for example, tetracyclines.Aminoglycoside antibiotics, such as streptomycin and gentamicin, interfere with the initial steps of protein synthesis by changing the shape of the 30S portion of the 70S prokaryotic ribosome.These interferences cause the genetic code on the mRNA to be read incorrectly (Gorgani et al., 2009).

Injury to the plasma membrane
The membranes of all cells are quite similar; those of bacteria and fungi differ from eukaryotic cells.These differences allow for selective action of antimicrobial agents (Willey et al., 2010).Certain antibiotics, especially polypeptide antibiotics, bring about changes in the permeability of the plasma membrane, these changes result in the loss of important metabolites from the microbial cell.For example, polymyxin B causes disruption of the plasma membrane by attaching to the phospholipids of the membrane (Cardoso et al., 2007).Amphotericin B and nystatin selectively inhibits microorganisms that possess ergosterol in their cell membrane and produce pores on the membrane through which ions and small molecules are lost (Palacios et al., 2010).

Inhibition of nucleic acid synthesis
A number of antibiotics interfere with nucleic acid synthesis by blocking synthesis of nucleotides, inhibiting replication, or stopping transcription (Todar, 2011).Some drugs with this mode of action have an extremely limited usefulness because they interfere with mammalian DNA and RNA as well.Examples of drugs that inhibit nucleic acid synthesis are rifampin, quinolones, nofloxacin, ciprofloxacin and actinomycin D. Ciprofloxacin and other quinolones bind to the A subunit of DNA gyrase and prevent supercoiling of DNA, thereby inhibiting DNA synthesis (Oliphant and Green, 2002).Rifampin inhibits synthesis of mRNA by binding to DNA-dependent RNA polymerase (Hartmann et al., 1967).Actinomycin D Adegboye et al. 3471 inhibits both DNA and RNA synthesis by binding strongly to duplex DNA and interfering with the passage of DNA and RNA polymerase (Vekshin, 2011).

Inhibition of essential metabolites synthesis
Anti-metabolites are substances that affect utilization of metabolites and therefore prevent a cell from carrying out necessary metabolic reactions.Several antibiotics acts as anti-metabolites; they block the functioning of metabolic pathways by competitively inhibiting the use of metabolites by key enzymes (Lamichhane et al., 2011).Sulfonamides and several other drugs inhibit folic acid metabolism by competing with para-aminobenzoic acid (PABA).In many microorganisms, PABA is the substrate for an enzymatic reaction leading to the synthesis of folic acids, a vitamin that functions as a co-enzyme for the synthesis of the purine and pyrimidine bases of nucleic acids and many amino acids.In the presence of sulfanilamide, the enzyme that normally converts PABA to folic acid combines with the drug instead of PABA (Focks et al., 2010;Proctor, 2008).This combination prevents folic acid synthesis and stops the growth of the microorganisms.Examples are, trimethoprim, sulfa drug (sulfanilamide and sulfamethaxozole), they have a high therapeutic index because humans do not produce folic acid, therefore exhibits selective toxicity (Willey et al., 2010).

MECHANISMS OF ANTIMICROMIBIAL RESISTANCE
The treatment of infectious diseases caused by microorganisms that have become resistant to commonly used antibiotics has become a major global health care problem in the 21st century (Luzhetskyy et al., 2007;Woolhouse, 2008).Microbial resistance to drugs was recorded early in the history of chemotherapy and post introduction of penicillin into medical practice; resistant bacteria emerged rendering the "magic drug" ineffective, a pattern the microbes maintained for many years (Arias and Murray, 2009;WHO, 2011).However, over the past decades microbes have proved themselves to be adapted at becoming resistant to each new antimicrobial agent produced by man (Bergstrom, 2011).Just as it has been possible to develop antibacterial agents to interfere with each critical step in the growth mechanism or in the production of the protective walls of bacteria, they have evolved novel mechanisms of resistance to thwart the antimicrobial attack.There are many different mechanisms by which microorganisms' exhibits resistance to antimicrobial agents.

Resistance based on altered receptors for a drug
Because most drugs act on a specific target such as protein, RNA, DNA, or membrane structure, microbes can circumvent drugs by altering the nature of this target, penicillin resistance is due to alterations in penicillin binding proteins (Arias and Murray, 2009).Resistance of bacteria to rifampin (Jassal and Bishai, 2009) develops because of altered DNA-directed RNA polymerase.A change of one amino acid in the beta subunit of DNAdirected RNA polymerase alters binding of rifampin.
Usually the degree of resistance is related to the degree that the enzyme is changed but does not correlate strictly with enzyme inhibition.This form of resistance which exists at a low level in any microbial population develops during treatment (Olofsson and Cars, 2007).Appearance of such resistance is not due to mutation event but rather to selection of a few that possess an RNA polymerase with poor affinity for rifampin.Such microorganisms are common among the enterobacteriaceae, which explains why urinary tract infection pathogens easily become resistance to rifampin (Jassal and Bishai, 2009).
Erythromycin and clindamycin resistance is associated with an alteration on the 50S ribosomal binding site (Dunkle et al., 2010).Sulfonamide-trimethoprim resistance among microbial pathogens was based on altered receptors for the drug (Jensen and Lyon, 2009).The presence of an altered or new dihydropeteroic synthetase with poor affinity for sulfonamides will preferentially bind para-aminobenzoic acid and preclude a block of the folate synthesis cycle.Sulfonamide resistance of this type can be due to point mutation or plasma derived causing synthesis of a new enzyme (Jensen and Lyon, 2009).A serious problem is the increase in resistance to trimethoprim and its analogue, which is plasmid and transposons-mediated and due to production of an altered dehydrofolate reductase (Wagenlehner et al., 2008).Vancomycin resistance mostly in Gram positive bacteria is due to changes in the binding sites of vancomycin from D-Ala-D-Ala to D-Ala-Dlactate dipeptide of the muramyl peptide in their peptidoglycan (Sieradzki and Markiewicz, 2004).

Decreased entry of antibiotics
The main target of most antibiotics lies in the cytoplasmic membrane or in the cytoplasm hence drugs must penetrate the outer layer of the cell envelope for activity.The resistance of some bacteria can be due to a mechanism that prevents the drug from entering the cell and acting on its target.The plasmid encoded multi-drug resistance gene, qacB from S. aureus mediates resistance to a number of classes of antimicrobial organic cations (Nakaminami et al., 2010;Pantosti and Venditti, 2009).The gene has shown to encode a protein qac BIII with 25 transmembrane segments (Nakaminami et al., 2010) that confers resistance via export of the antimicrobial agent thus preventing their cytoplasmic accumulation.Basically tetracycline resistance is due to a decrease in drug accumulation, a drug efflux mechanism in which decrease uptake and efflux occur simultaneously probably influences its development as well (Poole, 2007).Resistant free milieu loses the tetracycline they do accumulate.

Resistance by drug inactivation or destruction
Many microorganisms confer resistance by their ability to produce enzyme that inactivates or destroy action of antimicrobial agents.Many Gram-positive and Gram negative bacteria are resistant to chloramphenicol because they have chloramphenicol-transacetylase that acetylates hydroxyl groups of the antibiotic structure thereby inactivating it.The best known mechanism of bacterial resistance is that of penicillinase (Pantosti and Venditti, 2009).Subsequent resistance of staphylococci to penicillin was confirmed to be due to penicillinase.With the production of β-lactam antibiotics, it become more appropriate to designate these enzymes as β-lactamase since their attack on the β-lactam ring leads to drug destruction (Moya et al., 2009).Chromosomal mediated β-lactamase is present in many Enterobacter, Citrobacter, Klebsiella and Pseudomonas.Aminoglycoside-inactivating enzymes are able to add acetyl, adenyl and phosphoryl groups to inactivate the antibiotic (Boehr et al., 2003).

Synthesis of resistance or alternative pathways
The action of anti-metabolites can be circumvented if a microbe develops an alternative metabolic pathway or enzyme.Antibiotic resistance by way of alternative metabolic pathway is not uncommon with Pseudomonas and fungi.Koser et al. (2010) showed that the target enzymes produced by a mutant organism might change in respect to its sensitivity to the inhibitor while still functioning as the unchanged enzyme.Some thymidinerequiring streptococci failed to be inhibited by trimethoprim and sulfonamides.These organisms cause some urinary tract infections but fail to undergo the thymineless-death that occurs normally with bacteria exposed to these agents (Koser et al., 2010).Other bacteria produce adequate dTMP by alternative methods, and as a result survive exposure to the folic acid inhibitors (Willey et al., 2010).Sulfonamide and Trimethoprim resistance develops when microbes deviate from the usual patterns of folic acid synthesis.

SUPERBUGS
The emergence and reemergence of antimicrobial resistance among bacterial pathogens has a global negative impact on public health (Vila and Pal, 2010).Upon on the introduction of a new antibiotic into the market the development of resistant is simply a matter of time (Newman and G.M.C., 2007).Antibiotics use in clinical practices has been the major selective force for emergence and spreading of resistance gene (Edoh and Alomatu, 2007).Several other factors also contribute to this emergence and dissemination of antimicrobial resistance; among these are abuse of antibiotics, inadequate access to all antimicrobial agents, health care system, malnutrition and poverty (Caron and Mousa, 2010).
The development of resistant to more than one antibiotics is a major problem in the treatment of infectious diseases caused by pathogenic microorganisms (Mindlin et al., 2008;Nikaido, 2009).Over the past few decades, bacterial resistance to multiple antibiotics has become widely recognized as serious problem.These resistances make many diseases increasingly difficult if not impossible to treat.The rate at which the microorganisms are now developing resistance to the available antimicrobial agents is getting to an alarming rate.

Methicillin-resistant Staphylococcus aureus (MRSA)
Methicillin resistant S. aureus (MRSA) is a bacterium that causes different types of infections that are very difficult to treat in humans.This is because this bacterium has developed the mechanism to resist the action of antimicrobial agents such as penicillin, methicillin and cephalosporin (Klevens et al., 2006;Sakoulas and Moellering, 2008).S. aureus is a virulent pathogen that is responsible for a wide range of infectious diseases like bacteremia, endocarditis, osteomyelitis, meningitis, septicemia and pneumonia; has developed resistance to most common antibiotics in use especially that of the beta lactam class (Gould et al., 2010).Strains of S. aureus that are resistant to multiple antimicrobial compounds are major threat to public health care system (Jensen and Lyon, 2009).For many years, clinicians and public health officials have faced methicillin resistance S. aureus to many antibiotics in use (Baltz, 2009;Gould et al., 2010).MRSA infections are among the most virulent infections known; the superbug causes nearly 500,000 hospitalizations and 19,000 deaths in the United States each year, more deaths than caused by AIDS (Klein et al., 2007).The bug can be acquired in the community or in hospitals (Naimi et al., 2003).
Most MRSA infections occur in people who have been in hospitals or other health care facilities, such as nursing homes and dialysis centers.When it occurs in these settings, it is known as Health Acquired MRSA (HA-MRSA).HA-MRSA infections typically are associated with invasive procedures or devices, such as surgeries, intravenous tubing or artificial joints (Maree et al., 2007;Adegboye et al. 3473 Zell and Goldmann, 2007).However, people who have an open wound, abscess, boil or other type of puss-filled lesion are also susceptible to this pathogen.Communities Acquired MRSA (CA-MRSA) occurred in the wider community among healthy people, who are not immune compromised and have not had any medical procedure or stay in health care facility within the last year.It can be spread by skin to skin contact with infected person especially among groups such as wrestlers, high school students, child care workers and people who live in crowded conditions; or sharing of things such as towel and razor (Davis et al., 2007;Wang et al., 2008).Strains of MRSA had been reported to have developed resistance to vancomycin that was regarded as the last resort (Arias and Murray, 2009).Mechanisms of resistance in MRSA may be acquired or produces through mutations in genes or integration of certain genes (Ito et al., 2007).The presence of the plasmid gene (blaZ) that is able to produce β-lactamase enzyme confer resistant in S. aureus.This enzyme is able to hydrolyze the peptide bond in the β-lactam ring in the penicillin drugs, rendering the drug useless by not been able to bind to the transpeptidases which play important role in the cross-linking of the peptidoglycan subunits (Milheiriço et al., 2011).The emergence of MRSA is due to the acquisition of staphylococcal cassette chromosome mec element which carry a gene (mecA) which encodes a penicillin binding protein (PBP2a) with low affinity for β-lactam antibiotics (Abd El-Moez et al., 2011;García-Álvarez et al., 2011).MRSA resistant to antimicrobial agent quinolones is due to mutation, in either the GyrA subunit of gyrase or GrIA subunit of topoisomerases IV, this reduce quinolone affinity for its targets (Strahilevitz et al., 2009).Another mechanism of resistance is the presence of efflux pump which enables the bacteria to pump out the antibiotics from the cell (Poole, 2005).Strains of MRSA called Vancomycin Resistant S. aureus (VRSA) are able to resist due to the acquisition of the vanA gene cluster (Perichon and Courvalin, 2009).

Vancomycin-resistant Enterococcus species (VRE)
Vancomycin resistant Enterococci are of major health care concern due to their prevalence and ability to transfer resistance to other bacteria like in the case of Vancomycin resistant S. aureus (Zirakzadeh and Patel, 2006).Enterococci are normal flora of the gastrointestinal tract and the two major pathogenic Enterococci are E. faecalis and E. faecium (Chlebicki and Kurup, 2008).They have gained recognition as nosocomial pathogens and have developed resistance to many commonly used antibiotics like penicillin, cephalosporins, aminoglycosides, fluoroquinolones, licosamide and many others (Deshpande et al., 2007;Kuzucu et al., 2005;Rice, 2001).Among these resistances, the emergence of Sci.Res.Essays resistant against glycopeptides is of major clinical concern.Vancomycin resistance among Enterococci (VRE) was first recorded in England in 1988, and subsequent development arise worldwide (Uttley et al., 1988).Reports on VRE colonization and infections in hospitalized patients have tragically increased in countries all over the world (Huh et al., 2006;Kosack et al., 2009;Yilmaz et al., 2009).Retrospective study has suggested that the major carrier for VRE is the healthy population within a community (Robredo et al., 2000).
The reasons why Enterococci have become established in health care facilities is their intrinsic resistance to several commonly used antibiotics and their ability to acquire resistance either by mutation or acceptance of foreign genetic material through the transfer of plasmids and transposons (Qu et al., 2007).There are seven identified phenotypes of vancomycin resistance : vanA, vanB, vanC, vanD, vanE vanG and vanL (Boyd et al., 2008;Cetinkaya et al., 2000).The phenotypical naming of these Enterococci strains is based on their resistance to vancomycin and teicoplanin, the inductivity capacity of the resistance and the ability to transfer resistance to other organisms (Aznar et al., 2004).VanA and vanB have been seen in health facilities and have been major cause of serious infections (Kirdar et al., 2010;Sakka et al., 2008).
Mechanism of resistance of VRE: the vanA and other genes involved in the resistance (vanR, vanS, vanH, vanX and VanZ) reside on 10,581-bp transposon (Tn1546), which is found on a plasmid (Vilela et al., 2006).Regulation and expression of these genes results in the synthesis of abnormal peptidoglycan precursors terminating in D-alanine-D-lactate instead of D-alanine-Dalanine that contain pentapeptide intermediate structure and thus eliminate the glycopeptides target which was suppose to block the transglycosylation and transpeptidation reactions in the cell wall synthesis (Tenover, 2006).

Carbapenem-resistant Klebsiella pneumoniae (CRKP)
Carbapenem Resistant K. pneumonia is an emerging nosocomial pathogenic organisms and infections cause by this organism is of serious public health care concern (Falagas et al., 2007;Schwaber et al., 2008).K. pneumonia is a Gram negative pathogenic bacterium causing urinary tract infections, cholecytitis, pneumonia, osteomyelitis, wound infections, thromobophlebitis, septicemia and many others.This organism has gotten recognition worldwide due to its ability to produce extended-spectrum β-lactamases (ESBLs).CRKP is resistant to almost all available antibiotics and infections have caused high morbidity and mortality especially among hospitalized patients who are seriously ill and exposed to invasive device (Goren et al., 2010;Lledo et al., 2009;Schwaber et al., 2008).
Carbapenems has been the drug of choice used to treat serious infectious caused by K. pneumonia producing ESBLs (Song et al., 2009a).Carbapenem resistance in K. pneumonia has been ascribed to enzymatic activities by plasmid borne carbapenemases (Queenan and Bush, 2007).In addition to signifying resistance to carbapenems by K. pneumonia, is also associated with additional mechanisms of resistance to other antibiotics like cephalosporins and monobactams, this leads to the emergence of multi-drug resistance bug (Leavitt et al., 2007;Schwaber et al., 2008).
The resistance mechanism of Carbapenem Resistant K. pneumonia is the production of carbapenemase enzyme, bla KPC (Sidjabat et al., 2011).This gene that encodes the bla KPC resides on transposon which is mobile; this increases the risk for dissemination (Lledo et al., 2009).

Fluoroquinolone-resistant Pseudomonas aeruginosa (FRPA)
Fluoroquinolone-Resistant Pseudomonas aeruginosa is a leading cause of nosocomial infections in health care facilities worldwide (Lee et al., 2010;Zhanel et al., 2010).The spread of this organism in health care facilities is often difficult to control due to its ability to develop resistant to multiple classes of antibiotics, even during the course of treatment (Lister et al., 2009).P. aeruginosa is an opportunistic organism with high virulent index causing infections such as pneumonia, bacteremia, urinary tract infection, and wound infection especially among immunocompromised patients (Shams-Eldin et al., 2011).Both community acquired and hospital acquired infections caused by P. aeruginosa are of serious therapeutic challenge for treatment associated with high morbidity and mortality rates (Lambert et al., 2011;Shorr, 2009).
Fluoroquinolones show potency against a broad range of pathogens responsible for community-and hospitalacquired infections (Hooper, 2001;Polk et al., 2004).Broad use of these antibiotics had lead to the emergence of resistance organisms especially among Gram-negative bacteria (Zervos et al., 2003).Mechanism of resistance of P. aeruginosa to fluoroquinolones is predominantly due to point mutation in the DNA gyrase (gyrA and gyrB) and topoisomerases IV (parC and parE) genes (Maeda et al., 2011;Poole, 2011).This mutation makes it impossible for the fluoroquinolones to form complex with the DNA, thus not been able to block DNA replication (Poole, 2011;Tam et al., 2010).Plasmid resistance and efflux systems have also been reported in P. aeruginosa (Poole, 2005;Strahilevitz et al., 2009).

Cephalosporin-resistant Escherichia coli (CREC)
Pathogenic Escherichia coli are one of the leading causes of diarrhea and extraintestinal infections in humans with high morbidity and mortality rates due to outbreaks (Flock, 2011).The emergence of a new E. coli strain (E. coli 025:H4-ST131) have been reported in Europe, this superbug is been found to be resistant to eight different classes of antibiotics including cephalosporin (Woodford et al., 2009).Recently a new superbug E. coli 0104:H21 emerge in Germany causing hemolytic-uremic syndrome that result in epidemic (Gallagher, 2011).
The major mechanisms of resistance of cephalosporinresistant E. coli is the production of extended-spectrum βlactamases (ESBLs) which are synthesize by the presence of plasmid genes encoding for TEM-1, TEM-2, SHV-1 or SHV-8; they are able to hydrolyze the antimicrobial agent cephalosporin (Dhanji et al., 2010;Liu et al., 2007;Livermore et al., 2007).

CONCLUSION
The emergence of antimicrobial resistance by pathogenic organisms to some extent is inevitable because of the ability to adapt and survival as a living organism.One of their mechanisms of survival is antimicrobial resistance.But it is sadden that antimicrobial resistance by pathogenic organisms is spreading at astronomical rate even to once susceptible pathogen either through new mutations or the acquisition of new genetic materials from other organisms.
The challenges presented by these resistant pathogenic organisms can be effectively tackle by molecular epidemiology and molecular analyses of mechanisms of antimicrobial resistance; these will greatly help in developing new antimicrobial agents with different mechanism of action against the pathogenic organisms.