Antimicrobial Agents

Journal of Analytical & Pharmaceutical Research

Abstract Mini Review

The word antimicrobial was derived from the Greek words anti (against), micro (little) and bios (life) and refers to all agents that act against microbial organisms. Antimicrobial agent is a general term that is mainly concerned with antibiotics, Volume 4 Issue 3 - 2017 antibacterials, antifungals, antivirals and antiprotozoans. Antimicrobial agents Department of Pharmacy, Uttarakhand Technical University, are drugs, chemicals or other substances that are capable of acting by two modes India either kill (microbiocidal) or slow the growth of microbes (microbiostatic). Antimicrobial medicines can be classified according to the microorganisms they *Corresponding author: Mohammad Asif, Department of act primarily against. For example, antibacterials are used against bacteria and Pharmacy, Uttarakhand Technical University, GRD(PG)IMT, antifungals are used against fungi. Dehradun, 248009, Uttarakhand, India, Email: Keywords: Antimicrobial; Antibacterials; Antifungals; Microbiostatic; Microbiocidal; Bacteria; Fungi; Antivirals; Antiprotozoans; Penicillium Received: | Published:

February 13, 2017 March 20, 2017

Introduction Use of substances with antimicrobial properties is known to have been common practice for at least 2000 years. Ancient extracts to treat infection. More recently, microbiologists such as LouisEgyptians Pasteur and and ancient Jules GreeksFrancois used Joubert specific observed molds antagonism and plant for some bacteria and discussed the merits of controlling these interactions in medicine. In 1928, Alexander Fleming became the as Penicillium Rubens. The substance extracted from the fungus hefirst named to discover Penicillin a natural and in powerful 1942 it was antimicrobial successfully fungus used toknown treat a Streptococcus infections [1,2]. But nowadays, all over the world treatment of using antimicrobial agents is currently facing its own limitation, due to the development of resistance by the microbes over the period of time. Bacteria are involved in many aspects of and suffer from interactions with bacteria. For example we use bacteriaecology andfor making health. Ityoghurt, seems likelycurd, cheese that all and species other both fermented benefit foods and also large number of bacteria lives on the skin and Bacterial Cell Structure. in the digestive tract. The human gut contains more than 1000 Figure 1: bacterial species bacteria synthesize vitamins such as Folic Acid, Vitamin K and biotin and they ferment Cell Wall the complex, indigestible which are carbohydrates. beneficial [3]. OtherGut useful bacteria in Protects the cell and maintains its shape, bacteria can be sugar into Lactic Acid. Also bacteria play very important role in categorized according to their cell wall type: the medicine gut flora such include as vaccine Lactobacillus component species, and whichin the production convert milk of a. Gram positive walls are thick with little lipid. antibiotics, drugs, hormones, and antibodies. On the other hand walls are much thinner, with two layers. a pathogenic bacterium causes an enormous level of spoilage, b. Gram negative Some have a slimy layer of polysaccharides and suffering and death through the infection. The bacterial cells differs bacteria polypeptides, allowing them to attach to objects and providing dramatically in structure and function compared to mammalian protection. cells. The bacterial cytoplasm is separated from the external environment by a cytoplasmic membrane, as shown in Figure 70s ribosomes 1. The bacterial cell wall is chemically distinct from mammalian cell [4] walls and so is constructed by enzymes that often have no These are for performing protein synthesis. They are smaller direct counterpart in mammalian cell construction. The following than the 80s ribosomes in eukaryotic cells. Flagellum another are the functions of the various parts of the bacterial cell. optional feature is a projection that moves around to allow the

cell to move. A cell may have multiple flagella arranged around it.

Submit Manuscript | http://medcraveonline.com

Nuclear material Gram (–) bacteria. Schematic view of cell wall after Gram staining A folded mass of DNA and RNA, also called the nuclear zone have been classified into two main categories viz., Gram (+) and additional rings of genetic material that aren’t essential to the cell, is shown in Figure 3 [6]. often-containing contain all genes the genes for antibiotic required resistance. for vital functions. Plasmid are Mesosome An infolding of the membrane that is the site of respiration existence of the mesosome is disputed and most scientists believe (like a mitochondrion) - it’s shape improves surface area. The it isIn a mistakeaddition, in bacteria electron possess microscope a crucial technique. structure surrounding the entire cell, the Peptidoglycan (PG), which forms a sacculus around the bacterial cell, is an essential cell wall polymer since interference with its synthesis or structure leads to loss of cell shape and integrity followed by bacterial death. The peptidoglycan [5] layer as shown in Figure 2 consists of a matrix of polysaccharide chains composed of alternating (italics) N N

-acetylmuramic acid (MurNAc) -acetylglucosamine (GlcNAc) sugarClassification moieties cross-linked through pentapeptide sidechains. Hans christian gram: A Danish microbiologist, had developed the Gram stains in order to visualize bacteria more easily under Figure 2: Peptidoglycan layer. microscope. Based upon the staining pattern pathogenic bacteria

Figure 3: Gram+Ve and Gram-Ve Cell Wall.

The cell wall of gram (+): Bacteria although complex enough, Microorganisms are a group of organisms which include living (ex. (b) Bacteria, fungi, protozoans, algae of the cell is set of antigenic determinants which assists to organisms (ex. (v) Virus). adhereis simpler to particularthan that oftarget Gram cell. (-) Theorganisms. next barrier On the is thevery cell outside wall, etc.) as well as non-living Bacteria: Bacteria are unicellular organisms found in nature on cytoplasmic membrane and accounts for 50% of the dry weight of zero (psychrophiles) to up to 1000C (thermophilic). thespongy, bacterium. gel-forming Beneath layer, this i.e.layer peptidoglycan is the lipoidal layer cytoplasmic external cell to Bacteria all living and non-living things at temperature range from below membrane e.g. Staphylococci aureus, Streptococci pneumoniae, which they grow, on the basis of group of cells, depending on Bacillus subtilis . patogenecityare classified and according on staining. to the shapeOn the of ground cell, on of temperature staining they in With the gram[7] (-): Bacteria, the cell wall is more complex and Gram positive (Gram+ve) and Gram more lipoidal. These cells usually contain an additional, outer negative (Gram-ve). Gram positive bacteria shows violet color and membrane, which contains complex lipopolysaccharides that Gramare further negative classified bacteria asshows pink colour in a procedure called encode antigenic responses. Below this lies, less impressive, Gram Staining developed by C. Gram. Based on pathogenicity, layer of peptidoglycan this is followed by a phospholipid rich cytoplasmic membrane. e.g. Escherichia Coli, Haemophilus influenzae, Pseudomonas aeruginosa the classification is pathogenic disease/infection causing i.e. infectious and non-pathogenic-non infectious. In medicinal [7]. chemistry, this classification is important.

Citation:

Fungi: Fungi are universal in distribution. Many are terrestrial found on the skin, hair and nails. The fungus is a eukaryotic and thrive best in soil. Some live in tissues of plants and animals fungi grow animals and bacteria. Fungi contain unicellular, multinucleate on food stuffs such as bread, jams, pickles, fruits, and vegetables. organism which is classified as a separate kingdom from plants, Fungiwhile theare remaindersaprophytic is and found parasitic in aquatic in nature. places. Saprophytes Many grow reproductive spores and the nature of hyphae. They divide on dead organic matter, while parasites live on living bodies of sexuallyand multicellular or asexually forms or bythey both are ways. classified Fungi on are the almost basis entirelyof their other animals. Parasitic fungi include Candida albicans which is multicellular with exception of yeast Saccharomyces cerviseae the causative agent of Candiditis. which is prominent unicellular fungus. Fungi are heterotrophic, deriving their energy from another organism, whether alive or Protozoans: Protozoa are minute and acellular animalcules dead. Fungi are eukaryotic protista differing from bacteria in many without tissues and organs having one or more nuclei. They are ways, as they posses rigid cell wall containing chitin, mannan, free living or they remain in association with animals and plants. other polysaccharides and their cytoplasmic membrane contains Some which are parasitic in nature include protozoans Amoeba sterol. The major difference between fungal cells and plant cell is causing amoebiasis and causing Malaria. Plasmodium that fungal cell walls contain chitin, while plants contain cellulose Viruses: intracellular obligate parasites. They occupy position in between Viruses are acellular, micro-organisms which are [11-13]. interfering with: like plants, animals and bacteria for their survival. Viruses are The antifungal agents are classified according to their mode of inherentliving and intracellular non-living. Viruses parasites are of host living specific cells. and ex. depend M. poliomyelitis on hosts a. Cell wall synthesis, causes Poliomyelitis, HIV causes AIDS. b. Plasma membrane integrity, Infections by pathogenic microbes: Many microorganisms or c. Nucleic acid synthesis, microbes are pathogenic to plants, animals and human life causing various diseases resulting in extensive mortality and morbidity. d. Ribosomal function (Figure 4). Pathogenic microbes are microorganisms that cause infectious diseases. These organisms involved include pathogenic bacteria, causing diseases such as plague, tuberculosis, and anthrax; mode of action, viz, The classification of antifungal drugs are made upon their protozoa, causing diseases such as malaria, sleeping sickness and A. Systemic antifungal drugs: toxoplasmosis; and also fungi causing diseases such as ringworm, candidiatis or histoplasmosis. However, other diseases such as a. Polyenes antibiotics: Amphotericin B. b. Azole derivatives: (Imidazole: Ketoconazole, Miconazole; which are not living organisms. Pathogenic bacteria contribute to Triazole: Fluconazole, Itraconazole, Voriconazole, influenza, yellow fever or AIDS are caused by pathogenic viruses, other globally important diseases such as pneumonia caused by Posaconazole, Ravuconazole). Streptococcus and Pseudomonas and food borne illnesses, which can be caused by bacteria such as Shigella, Campylobacter and c. Echinocandin: Capsofungin, Anidulafungin, Micafungin. Salmonella. Pathogenic bacteria also cause infections such as d. Antimetabolite: tetanus, typhoid fever, diphtheria, syphilis and leprosy [8]. Each parasitic species has a characteristic interaction with their hosts. e. Nikkomycin. Flucytosine (5-FC). Microorganisms like Staphylococcus or Streptococcus species which cause skin infections pneumonia, meningitis and other forms of B. Topical antifungal drugs: surface infections. On the other hand, many organisms are part a. Polyene antibiotics: Amphotericin B, Nystatin, Hamycin, Natamycin, Rimocidin, Hitachimycin, Filipin. tract, intestine etc. without causing disease. But sometimes these becameof normal opportunistic flora of human parasite body and that led exist to infectionson skin, nose, [9]. Obligate urinary b. Azoles: Clotrimazole, Ketoconazole, Miconazole, Econazole, intracellular parasites such as, Rickettesia and Chlamydia are Butaconazole, Oxiconazole, Sulconazole, Fenticonazole, able to grow and reproduce only within host cells. Some species Isoconazole, Bifonazole, Terconazole. such as Pseudomonas aeruginosa, Burkholderia cenocepacia c. Others: Tolnaftate, Undecyclinic acid, Povidone and Mycobacterium avium are parasitic when individual iodine, Triacetin, Gentian violet, Sodium thiosulphate, Cicloporoxolamine, Benzoic acid, Quinidochlor. infection/infectioussuffering from immune microorganism suppression is or a continuouscystic fibrosis process cells in [10]. the C. Systemic antifungal drugs for superficial infections: Development of new therapeutic agents to treat or to fight these clinical medicine. With the advent of antibiotic resistant strains, a. Heterocyclic benzofurans: Corticofunvin, Griseofulvin. synthesis of new drugs has become one of the main objectives of researchers across globe. b. Allylamine:

Antifungal Agents: An antifungal agent is a drug, chemicals or Mycology: The discipline Terbinafine, of biology Butenafine, which Naftifine.is devoted to the study other substances that selectively eliminates fungal pathogens from of fungi is known as mycology. Mycology is concerned with the a host with minimal toxicity to the host, which is most commonly systematic study of fungi, including their genetic and biochemical

Citation:

properties. Mycoses affecting humans can be divided into four d) Systemic or deep mycoses: Are caused by primary groups based on the level of penetration into the body tissues as pathogenic and opportunistic fungal pathogens. The primary [14,15]. pathogenic fungi cause infection in a normal host; whereas, aused by growing only on a) Superficial mycoses: C fungi host in order to establish infection (e.g., cancer, surgery the outermost surface of the skin or hair. An example of a andopportunistic AIDS). The pathogensprimary pathogens require usually immune gain depressant access to fungal infection is Tinea Versicolor, a fungus infection that the host via the respiratory tract and include Coccidioides commonly affects the skin of young people, especially the immitis, Histoplasma capsulatum, Blastomyces dermatitidis chest, back, upper arms and legs. and Paracoccidioides brasiliensis. The opportunistic fungi b) Cutaneous mycoses or dermatomycoses: Caused by fungi invade via the respiratory and alimentary tract, and include Cryptococcus neoformans, Candida spp., Aspergillus spp., causing infections commonly known as athlete’s foot, jock Penicillium marneffei, Zygomycetes, Trichosporon beigelii and itchgrowing and ringworm.only in the superficial layers of skin, nails, and hair Fusarium spp. c) Subcutaneous mycoses: Caused by fungi penetrating below Mycology-pathogenic fungi: The study of pathogenic fungi is the skin in the subcutaneous, connective, and bone tissue. referred to as medical mycology. Pathogenic fungi cause disease in The most common is sporotrichosis, occurring amongst humans or other organisms. The commonly observed pathogenic gardeners and farmers who come in direct contact with soil. fungi are enlisted below,

Figure 4:

Classification of antifungal agents by their mode of action. Candida: Candida species are important human pathogens Aspergillus: The aerosolized Aspergillus spores are found almost causing opportunist infections in immune compromised hosts everywhere around human being and generally does not possess (AIDS sufferers, cancer patients and transplant patients). The health issues. But still Aspergillus is capable of causing disease in three major ways: by the production of mycotoxins; by the induction of allergenic responses; and lastly by the localized casesinfections caused caused by theby the systemic Candida infections. species are Fungal difficult species to treat of andthe or systemic infections. Aspergillus flavus produces mycotoxins, genuscould beCandida fatal. Candidagenerally species live communally alone account on and to 30-40%in the human death body. There is increase in development of drug resistance by ability to contaminate foodstuff such as nuts. Candida species to current therapies, motivating researchers to aflatoxin which can act as both toxin and a carcinogen, having The majorities of are found in understand their genetics and discover new therapeutic targets. Cryptococcus: Cryptococcus species

Citation:

the soil and generally do not cause disease in humans. Exception capabilities, destroying the cell walls or by modifying the fungal is Cryptococcus neoformans which cause disease in immune DNA and altering the cell functioning. Antifungal resistance has depressant patients like AIDS, causing a severe form of meningitis

beena. traditionallyPrimary (intrinsic), classified as three types Histoplasma: Histoplasma capsulatum can cause histoplasmosis and meningo-encephalitis. b. in humans, dogs and cats. The infection is usually due to inhaling the contaminated air and is prevalent. c. SecondaryClinical resistance. (acquired), Pneumocystis: Pneumocystis jirovecii can cause a form of In the last decade, microorganisms are becoming drug resistant pneumonia in people with weakened immune systems, such as at a much faster rate than the rate of discovery of new drugs. The the elderly, AIDS patients and premature born children. drug resistance of fungi is importunately observed in patients with weak immune system suffering from diseases like AIDS and Stachybotrys: Stachybotrys chartarum can cause respiratory cancer. The researchers thus face a major challenge to develop damage and severe headaches, in houses that are persistently new, safe and more effective antifungals taking into account the damp. increase in opportunistic infections in the immune compromised Fungal infection prominent in particular diseases: The host. This can be overcome by the discovery of new drugs acting association of most commonly occurring fungi along with the patient suffering from the particular disease is enlisted below, byHistoric novel mechanismsperspective: of action [16-18]. a. Candida species, Aspergillus species, Phycomyces species: Leucopenia. sporotrichosis In 1903, de Beurmann and Gougerot infectionswere the by first using to discussointment. the In use the mid of potassium 1940s sulfonamides iodide to were treat b. Zygomycetes, Rhizopus, Mucor, Absidia: Diabetes. used to treat . paracoccidioido Whitfield in 1907mycosis treated though superficial they had limited fungal c. Candida, Cryptococcus, Histoplasma: Malignancies and Hodgkin’s disease. for treatment with high relapse rate. This was followed by the commercialefficacy towards use fungistaticof penicillin properties in the 1940s. and required In rapid longer succession, times d. Candida, Cryptococcus, Histoplasma: AIDS. came the discovery and development of streptomycin in 1944 and Clinically significant fungi and the site they affect: The pathogenicity and virulence of fungi causing infections, in humans was discovered in 1944. It was followed by the discoveries of is major concern in clinical world which focuses on the major Benzimidazole the first azole to have notable antifungal activity causative agents of disease, particularly Candida, Cryptococcus Hydroxystilbamidine, an antiprotozoal agent having antifungal and Aspergillus spp. The large diversity of potentially harmful actionChloramphenicol was used to in treat 1947 blastomycosis and chlortetracycline. In 1951 Hazen in 1948. and In Brown, 1948 fungi existing outside these groups, though rare may still posses potential to be more important than the common clinical fungi. used topical and oral polyene. In 1952 substituted benzimidazole fungi are enlisted as compoundsdiscovered the were first foundpolyene to antibiotic have antifungal called nystatin, properties. commonly The below, macrolides were developed in 1952 having bacteriostatic The site affected by the clinically significant properties. In 1956 Gold et al. reported the antifungal properties a. Malassezia furfur and Exophiala werneckii b. Piedraia hortae and Trichosporon beigelii: Hair. effective systemic antifungal. It became the standard and soon it : Superficial skin. replacedof the polyene hydroxy amphotericin stilbamidine. B, Amphotericin which was the B enjoyed first significantly the prime c. Microsporum species: Skin and hair. status of only antifungal agent available to treat systemic mycoses for nearly decade against which newer therapies for systemic d. Epidermophyton species: Skin and nails. e. Trichophyton species: Skin, hair and nails. an antifungal agent who had failed to provide favorable results for mycoses were compared. In 1957 Flucytosine, was developed as : f. Sporothrix schenckii, Cladosporium species often developed fungal resistance which led to use in combination Chromoblastomycosis. the use as cytostatic agent. The use offlucytosine as a monodrug g. Histoplasma capsulatum, Penicillium species: Systemic Griseofulvin was developed in respiratory. with Amphotericin B to overcome the resistance. The first mycoses.significant Before oral antifungal Griseofulvin agent h. Blastomyces dermatitidis: Subcutaneous/respiratory. Dermatophytoses1958, which became was availableonly by the for topical the treatment drugs which of superficial were not i. Cryptococcus neoformans: Respiratory/CNS. especially effective against Tinea, capitis the treatment and Onychomycosis. of superficial The

Antifungal resistance: The development of drug resistance were developed from 1958 onwards. The development of in fungi is a broad concept, which describes failure of current semi-synthetic Penicillin’s, Cephalosporin’s and Glycopeptides antifungal therapy to overcome the fungal infection. The antifungal range of cutaneous Mycoses. In the 1960s, Thiabendazole and therapies are designed to eradicate fungal infection by various MebendazoleChlormidazole were as a reported 5% cream to havein 1958, antifungal was beneficial and antihelminthic over wide mechanisms of action, like by disrupting their reproductive properties. In 1969 the imidazoles, clotrimazole and miconazole

Citation:

were introduced, which was soon followed by econazole in William Foye (1996) Principles of Medicinal Chemistry. J Med Chem

7. 8. 39(7):http:// 1567-1568. www.wikipedia.org/microbes 1974. The allylamines discovered in dermatomycoses1974 are the other, including classes of antifungal drugs that have a significant impact on antifungal 9. Pankey GA, Sabath LD (2004) Clinical relevance of bacteriostatic therapy especially for superficial Onychomycosis. Ketoconazole was developed in 1977 and since versus bactericidal mechanisms of action in the treatment of Gram- andhas becomeItraconazole the standard (1984) among were thediscovered. azoles. In Intensivethe mid-1980s research two 10. positiveChu Daniel bacterial TW, infections.Plattner ClinJacob Infect J (1996) Dis 38(6): New 864-870. Directions in broad-spectrum, orally available triazoles, Fluconazole (1982) resulted into introduction of three azoles Voriconazole (2000), th 11. AntibacterialAnantnarayan Research. R, Paniker J Med CKJ (2009)Chem 39(20): Textbook 3853-3874. of Microbiology. (8 began between 1990-1999 to develop new antifungal agents and edn), University Press Publication, Hyderabad, India. three new echinocandins (Caspofungin (2002) Anidulafungin th (2004),Posaconazole Micafungin (2005)-Schering-Plough, (2006) for theirclinical Ravuconazole use [19,20]. (2007) and 12. edn), Japyee Brothers Medical publishers (P) Ltd, New Delhi India, pp. Tripathi KD (2003) Essential of Medical Pharmacology. (5 Conclusion 625. Williams DA, Lemke TL (2002) Foye’s Principles of Medicinal Antimicrobial agents act against bacterial infection either by Chemistry. (5th edn), Williams and Wilkins, Philadelphia, USA, pp. killing the microbes or by arresting its growth. They do this by 13. targeting DNA and its associated processes, attacking metabolic nd processes including protein synthesis, or interfering with cell wall 14. 712. synthesis and function. Antimicrobial drugs are important class of 15. Ronald PK (2007) Dermatology. (2 edn), pp. 1135. chemotherapeutic drugs. Compounds are organized according to their target, which helps the reader understand the mechanism of Frank CO, Brown A, Gow NA (2003) Antifungal agents: mechanisms 16. Gauwerky K, Boreli C, Korting HC (2009) Targeting virulence: a new action of these drugs and how resistance can arise. of action. Trends Microbiol 11(6): 272-279.

References paragigmGupte M, Kulkarnifor antifungals. P, Ganguli Drug BN Discov (2002) Today Antifungal 14(3-4): antibiotic. 214-222. Appl 1. https://www.doctorfungus.org 17. 18. Sanglard D (2002) Modern Fungicides and Antifungal Compounds. 2. http://www.wikipedia.com Microbiol Biotech 58(1): 46-57. Zoetendal EG, Vauhan EE, de Vos WM (2006) A microbial world 19. CurrGupta Opin AK, MicroSauder 5: DN, 379-385. Shear NH (1994) Antifungal agents: an over 3. 4. Foye W, Thomas L (1995) Principles of Medicinal Chemistry. (4th within us. Mol Microbiol 59(6): 1639-50. 20. Crandall MA (2010) Pharmaceuticals: Antifungal Drugs, edn), Waverly P Ltd, New Delhi, India. view part 1. J Am Acad Dermatol 30(6): 677-698. Technologies and Global Markets, BCC Research. 5. nd edn), ASM press, Washington, USA. Cooper GM, Robert EH (2013) The Cell: A Molecular Approach. (2 6. function of the Mur enzymes: development of novel inhibitors. Mol EI Zoerby A, Sanschagrin F, Levesque RC (2003) Structure and

Microbiology 47(1): 1-12.

Citation:

Asif M (2017) Antimicrobial Agents. J Anal Pharm Res 4(3): 00104. DOI: 10.15406/japlr.2017.04.00104