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G Model MICRES-25661; No. of Pages 9 ARTICLE IN PRESS Microbiological Research xxx (2014) xxx–xxx Contents lists available at ScienceDirect Microbiological Research journal homepage: www.elsevier.com/locate/micres Review Treatment of infectious disease: Beyond antibiotics Anshul Nigam a,∗,1 , Divya Gupta b,1 , Ashwani Sharma c a IPLS Building, School of Life Science, Pondicherry University, Puducherry 605014, India Department of Biotechnology, Mangalayatan University, Beswan, Aligarh, Uttar Pradesh 202145, India c Computer-Chemie-Centrum, Universität Erlangen-Nürnberg, Nägelsbachstr. 25, 91052 Erlangen, Germany b a r t i c l e i n f o Article history: Received 16 July 2013 Received in revised form 9 December 2013 Accepted 23 February 2014 Available online xxx Keywords: Phages Bacteriocins Killing factors Non-antibiotic drugs Quorum quenching a b s t r a c t Several antibiotics have been discovered following the discovery of penicillin. These antibiotics had been helpful in treatment of infectious diseases considered dread for centuries. The advent of multiple drug resistance in microbes has posed new challenge to researchers. The scientists are now evaluating alternatives for combating infectious diseases. This review focuses on major alternatives to antibiotics on which preliminary work had been carried out. These promising anti-microbial include: phages, bacteriocins, killing factors, antibacterial activities of non-antibiotic drugs and quorum quenching. © 2014 Elsevier GmbH. All rights reserved. Contents 1. 2. 3. 4. 5. 6. 7. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Phage therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Mode of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Advantages and disadvantages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bacteriocins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Mode of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Advantage and disadvantage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Killing factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Antibacterial activities of non-antibiotic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Advantage and disadvantage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Quorum quenching . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Advantage and disadvantage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Introduction Microbial ecosystem is highly vivacious system and each species tries to excel in competition, the intra species competition is also fierce. Microbes foray over each other through chemicals to overcome competition. Humans had exploited these chemicals to cure various kinds of infectious diseases. Following the ∗ Corresponding author. Tel.: +91 413 2654520; mobile: +91 9486374847. E-mail address: [email protected] (A. Nigam). 1 Equally contributing authors. 00 00 00 00 00 00 00 00 00 00 00 00 00 00 discovery of penicillin in 1928 by Scottish scientist and Nobel laureate Alexander Fleming; antibiotics have come a long way to cure infectious disease (Bennett and Chung, 2001). Today more than 100 different kinds of antibiotics have been discovered. The antibiotics have been found to cure various kind of infectious disease caused by microbes, but the advent of drug resistance in them, also known as ‘superbugs’ has pose new challenges for researchers (Dong et al., 2007; Livermore, 2004a; Williams, 2002). The rise and spread of drug resistance is attributed to evolutionary selection against antibiotics and high human mobility across globe (Heinemann, 2000; Levy and Marshall, 2004). Few prominent examples of acquired drug resistance include methicillin resistant http://dx.doi.org/10.1016/j.micres.2014.02.009 0944-5013/© 2014 Elsevier GmbH. All rights reserved. Please cite this article in press as: Nigam A, et al. Treatment of infectious disease: Beyond antibiotics. Microbiol Res (2014), http://dx.doi.org/10.1016/j.micres.2014.02.009 G Model MICRES-25661; No. of Pages 9 ARTICLE IN PRESS A. Nigam et al. / Microbiological Research xxx (2014) xxx–xxx 2 Staphylococcus aureus, fluoroquinolone-resistant S. aureus (Kaatz, 2005), erythromycin resistant Streptococcus pyogenes and S. pneumoniae (Frimodt-Møller et al., 2001) and vancomycin resistant enterocci (Kayser, 2003). Microbial resistance against antibiotics is a serious global health issue and has been recognized by number of reviewers (Berger, 2002; Dancer, 2001; Levy, 2001; Livermore, 2004b). The levels of resistance had continue to rise ever since it was discovered in year 2000, the World Health Organization alerted that infectious diseases may become non curable owing to high levels of multiple drug resistant pathogens (World Health Organization; Press Release WHO/41. http://www.who.int, 2000). The mechanism of antibiotic action may be owing to inhibition of protein synthesis, DNA damage and cell wall biosynthesis (Walsh, 2000). While antibiotic resistance is conferred in microbes through variety of mechanisms, it may arise through the selection of pre-existing types, species and variants (Livermore, 2003). The resistance may also arise through mutation or DNA transfer. Mutation(s) can confer resistance to the microbes against antibiotics through variety of mechanisms. It may alter the antibiotic target or reduce its permeability or increase its efflux (Van Bambeke et al., 2003) or might up regulate an antibiotic-inactivating enzyme or bypass an enzymatic pathway. Gene transfer through plasmids and transposons, can spread resistance horizontally. The gene blaTEM , which encodes TEM-1 -lactamase, is the most common ampicillin-resistance determinant and has spread widely through this mechanism (Livermore, 2004a). Few species incorporate DNA released from dead cells of related species, resulting in modification of their own genes, Penicillin resistance in pneumococci has mainly spread through this mechanism (Spratt, 1994). This review focuses on the alternatives to the antibiotics on which scientific community has been looking forward for years to overcome the problem of drug resistance. Following are major classes of alternatives: a. b. c. d. e. Phages Bacteriocins Killing factors in microbes Antibacterial activities of non-antibiotic drugs Quorum quenching 2. Phage therapy Phage’s represent distinguish set of viruses that infect bacteria. The earliest mention of phages dates back to 1896, Ernest Hankin, a British bacteriologist, reported that an unidentified substance that passes through bacterial filters possessed antibacterial activity. The observations of Hankin were further investigated by others microbiologist. It was Felix d’Herelle who coined the term bacteriophage and demonstrated its clinical utility in treating infection. Among all the alternatives to antibiotics mentioned in the review, phages not only went to clinical trials but also were produced at large scale during 1940s. The phages were administered to humans (i) orally, (ii) rectally, (iii) locally, (iv) as aerosols or intrapleural injections, and (v) intravenously (Sulakvelidze et al., 2001). Although presently phage therapy is out of fashion from all over the world but it still continues in Georgia (former Soviet Republic). This drop in phage therapy is majorly attributed to the fact that phage’s were applied for therapeutic purpose even before being fully understood. The application of phages as antimicrobials was pushed to brink with the advent of antibiotics (Kutter et al., 2010) 2.1. Mode of action Bacteriophages replicate follow two distinguish modules: (A) Lytic module: It comprises of following steps: (B) Attachment (C) Injecting phage DNA into the bacterial cell (D) Synthesis of bacterial components terminates (E) Replication of phage DNA, and production of new capsids (F) Phage components are assembled and released (lysis) (Fig. 1). (G) Lysogenic module:Steps I, II, IV and V are similar to those of lytic phase (i.e., attachment, injection and release). The III step involves integration of DNA into the host chromosome (lysogenization) which replicates along with host DNA for several generations (prophage). The prophage after several generations may break free from bacterial genome to induce cell lysis producing new phage particles (Fig. 1). Due to the long infection cycle, lysogenic phages are unsuitable candidates for phage therapy (Lorch, 1999). Phages impart their resistance to bacterial restriction enzyme through genome modification (Andriashvili et al., 1986). 2.2. Advantages and disadvantages The phages had been produced at commercial level for few years for therapeutic purpose (Summers, 1999) but their efficacy had always being questioned (Eaton and Bayne-Jones, 1934; Krueger and Scribner, 1941). This may be owing to the fact that scientist involved in discovery of phages were over enthusiastic about its application as bactericidal agent had overlooked clinical data (Kutter et al., 2010). The most interesting phenomenon associated with phages is that of auto dosing. It happens because phages are self replicating inside the bacterium host (Abedon and Cameron, 2010). High specificity is a major advantage as well as disadvantage associated with phages. Although it ensures minimal damage to health friendly micro flora (Skurnik et al., 2007; Gupta and Prasad, 2011) but at the same time it is necessary to identify disease causing bacterium, limiting their usage for presumptive treatment (LocCarrillo and Abedon, 2011). Similar constraints are not associated with antibiotics. Efforts are on to identify phages acting against broad spectrum of bacteria (Jensen et al., 1998; Melo et al., 2014) or to genetically modify them to enhance their spectrum of action (O’Flaherty et al., 2005; Merril et al., 2007). The major side effect associated with phage therapy is considered due to the release of endotoxins from bacteria lysed in vivo by the phages (Lorch, 1999). Even though the phage therapy is applied in few geographical locations over the decades and lot of research had been carried out with clinical perspective. However, bacterial immunity in this scenario had never been explored. The bacterial immune response may be innate or adaptive. The former response is either mediated through restriction modification that aids in differentiating between self and foreign DNA on basis of methylation pattern or lack of machinery required for phage replication (Abedon, 2012). Albeit innate immunity in bacteria was discovered decades ago however discovery of adaptive immunity began in late 80s when CRISPR (clustered regularly interspaced short palindromic repeats) sequences were identified in E. coli (Ishino et al., 1987; Nakata et al., 1989). The linkage of CRISPR sequences with adaptive immunity, nonetheless, was established only in previous decade. It is interesting to note that CRISPR mediated immune response involves gene silencing mechanism and is also inheritable (Barrangou et al., 2007; Brouns et al., 2008; Hale et al., 2009). We emphasize that clinical manifestation of bacterial immunity over phages must be evaluated prior to their application as antibacterial agent. Please cite this article in press as: Nigam A, et al. Treatment of infectious disease: Beyond antibiotics. Microbiol Res (2014), http://dx.doi.org/10.1016/j.micres.2014.02.009 G Model MICRES-25661; No. of Pages 9 ARTICLE IN PRESS A. Nigam et al. / Microbiological Research xxx (2014) xxx–xxx 3 Fig. 1. Lytic and lysogenic modules of phage infecting bacteria, the lytic module involves injecting of phage DNA into the cell followed by its replication, protein synthesis, packaging and release. The lysogeny module involves integration of phage DNA into microbial DNA that replicates along with cell DNA which can enter into lytic phase on stimuli. 3. Bacteriocins Bacteriocins are the bactericidal peptides secreted by many varieties of bacteria for the purpose of elimination of competition in milieu and were discovered by Gratia, 1925. It was demonstrated that E. coli strain V produced a dialyzable and heat-stable substance (later known as colicin V) that inhibits the growth of E. coli ϕ at very low concentration. These peptides may or may not post translationally modified (Guder et al., 2000; Pons et al., 2002; Sahl et al., 1995; Yorgey et al., 1994). Till date application of bacteriocins is limited to food preservation (Cleveland et al., 2001; O’Sullivan et al., 2002) although their indirect application in the form of probiotics is widely recognized. The probiotic bacteria produce bacteriocins that eliminate pathogenic microbes. 3.1. Mode of action Bacteriocins have been classified into four major classes on basis of their structure (Heng et al., 2007): Class I (antibiotics) are small (<5 kDa) heat-resistant peptides; Class II consists of small (<15 kDa), heat-stable, membrane active, unmodified peptides (Sablon et al., 2000); Class III consists of heat-labile proteins with sizes in excess of 15 kDa and Class IV, consists of complex bacteriocins with lipid or carbohydrate moieties bound to it (Garneau et al., 2002; Klaenhammer, 1993; Nes et al., 1996; Pag and Sahl, 2002; Sahl et al., 1995; Sahl and Bierbaum, 1998). Bacteriocins interact with the cell membrane and alter its properties leading to cell death. Owing to the same reason these are found to be more active against Gram positive bacteria compared to the Gram negative. Gram negative bacteria possess an outer membrane composed mainly of lipopolysaccharides (LPS). This outer membrane prevents free diffusion of molecules above 0.6 kDa while the smallest known bacteriocin is of 3 kDa size (Klaenhammer, 1993; Stiles and Hastings, 1991). However, some bacteriocins possess ability to be transported through receptors present on outer membrane (OmpF, FhuA) as well as on inner membrane (SbmA, YejABEF, TonB) of Gram negative bacteria (Cotter et al., 2013) subsequently bringing to cell death. Although Gram negative bacteria are not susceptible to bacteriocin, but removal of LPS make them sensitive towards bacteriocins (Stevens et al., 1991). The exact mode of action of bacteriocin over cell membrane is variable. Bacteriocin may bind to lipid-II, which play essential role in transporting peptidoglycan subunit from cytoplasm to cell wall ultimately interrupting cell wall synthesis leading to cell death. Alternatively, bacteriocin can cause pore formation in cell wall using lipid-II as a docking molecule (Cotter et al., 2005). Bacteriocins action can cause membrane de-energizing and dissipate proton motive force (PMF) leading to cell death (Fig. 2). It had been observed in many investigations that lantibiotics treated cells possess lower membrane potential (Jack et al., 1995). Bacteriocin may act by preventing uptake of amino acids and trigger their release from the cell (Hugenholtz and de Veer, 1991) or it may lead to exclusion potassium ions, depolarization of the cytoplasmic membrane, hydrolysis and partial efflux of cellular ATP (Abee et al., 1994; Chikindas et al., 1993). Although some bacteriocin are reported to act by mechanism not involving cellular membrane. Studies had reported bactericidal activity of bacteriocin through endonuclease activity on sensitive cell (Pugsley, 1984). The potential applications of the bacteriocins as antibiotics have been reviewed by Gillor et al., 2005 (Table 1). 3.2. Advantage and disadvantage Bacteriocins are found to active against many important human pathogens. Although they target narrow range of bacteria but their major advantage is that they can act without affecting much of the Please cite this article in press as: Nigam A, et al. Treatment of infectious disease: Beyond antibiotics. Microbiol Res (2014), http://dx.doi.org/10.1016/j.micres.2014.02.009 G Model MICRES-25661; No. of Pages 9 ARTICLE IN PRESS A. Nigam et al. / Microbiological Research xxx (2014) xxx–xxx 4 Fig. 2. Mechanism of action of various classes of bacteriocin. Class-I molecules can directly penetrate the cell membrane affecting cells integrity. Some of the Class I molecules interact with lipid II and inhibit cell wall synthesis. Class II molecules binds to the pore forming receptor as (Man-PTS) Mannose phosphotransferase system and induce pore formation. As some class-II molecules are amphiphilic in nature can penetrate the cell membrane affecting cells integrity. Class-III molecules directly induce cell lysis by affecting cell wall. natural microbiota of the body, when compared to other antibiotics. They have gathered attention owing to ever increasing problem of antibiotic resistance (Lohans and Vederas, 2011). Further, bacteriocins are easily degraded to simple non-toxic amino acids by proteolytic enzymes (Aasen et al., 2003; Tolinački et al., 2010) thus they may not be as long-lasting as antibiotics. However this problem may be subdued by usage of specialized drug delivery systems (Dicks et al., 2011) or peptide modification in form of dendrimers (Tam et al., 2002; Bracci et al., 2003) that may prevent degradation and deliver them at site of infection manifestation. Moreover, extensive use of bacteriocin can also confer its resistance in bacterial cells like antibiotics which is threating scientist for its usage on large scale. Genetically bacteriocin resistance is acquired through immunity gene present in producer strain. This immunity gene is either located on same bacteriocin producing operon or on mobile genetic elements (McKay and Baldwin, 1984; Froseth et al., 1988), that is, plasmid/transposon. Immunity genes located on mobile genetic elements are subjected to horizontal gene transfer to same or different species organisms enabling them to resist respective bacteriocins (Dicks et al., 2011). The resistance against bacteriocin may also acquire by alteration of gene expression. L. monocytogenes resistance towards class II bacteriocins had been linked with down regulation of a mannose permease (Ramnath et al., 2000; Gravesen et al., 2002; Cotter et al., 2005). Later on it was deciphered that the permease acts as a channel for class II bacteriocins (Diep et al., 2007). Multi drug efflux pump too confer resistance to bacteria like Cme ABC confers resistance to Campylobacter against bacteriocin OR7 (Hoang et al., 2011). Cross resistance between different bacteriocins had been observed presumably due to similar resistance mechanism. Table 1 Bacteriocins demonstrated as potential antibiotic agents in following investigations (selective examples are taken from review of Gillor et al., 2005). Bacteriocin Producer strain Infectious disease Reference Epidermin Gallidermin Lacticin 3147 Lanthiopeptin Mersacidin Nisin S-35 Staphylococcus epidermidis Staphylococcus gallinarum Lactococcuslactis Streptoverticilliumcinnamoneum Bacillus subtilis Lactococcuslactis Pseudomonas aeruginosa Dermal infections Dermal infections Mastitis infections Herpes simplex virus Vancomycin resistant strains Antimicrobial for inhibiting multi-drug resistant pathogens Treating pulmonary infections Allgaier et al., 1986 Kellner et al., 1988 Ryan et al., 1998, 1999 Naruse et al., 1989 Bierbaum et al., 1995 Severina et al., 1998 Nakayama et al., 2000 Please cite this article in press as: Nigam A, et al. Treatment of infectious disease: Beyond antibiotics. Microbiol Res (2014), http://dx.doi.org/10.1016/j.micres.2014.02.009 G Model MICRES-25661; No. of Pages 9 ARTICLE IN PRESS A. Nigam et al. / Microbiological Research xxx (2014) xxx–xxx 5 Crandall and Montville, 1998 demonstrated that L. monocytogenes acquiring Nisin resistance were also resistant to pediocin PA-1 and leuconocin S. The resistance against bacteriocin can also be acquired by inducing changes in membrane/cell wall (Crandall and Montville, 1998). These changes include: (1) alteration of membrane fatty acid/phospholipid composition or its charge/fluidity, (2) cell wall thickness/charge (Dicks et al., 2011). Hence a thorough evaluation of bacteriocin resistance is needed prior to their application at clinical level. 4. Killing factors Killing factors is the term used to define factors released by bacterial cells to kill sibling cells during starvation. This phenomenon attracted interest of scientific community as it is equivalent to cannibalism in higher species. It is best studied in B. subtilis; it contains a set of genes for “cannibalism” that induces lysis of its sister cells in its milieu during nutrient scarcity (Claverys and Håvarstein, 2007; Ellermeier et al., 2006; Engelberg-Kulka et al., 2006; González-Pastor et al., 2003; López et al., 2009). The nutrients released from the lysed cells are utilized by the killer cells for survival and spore formation. It is important to note that B. subtilis prefers predation over cannibalism, that is, it preferentially lyse the bacterial cells of other species (Nandy et al., 2007). The species on which B. subtilis predates include E. coli, P. aeruginosa, A. lwoffi, X. campestris and X. oryzae (Lin et al., 2001; Nandy et al., 2007). The feature of cannibalism in Bacilus subtilis is attributed to two peptides sporulation delaying protein and sporulation killing factor. Spo0A, a master transcriptional regulator that is known to regulate biofilm formation and sporulation also regulates synthesis of these peptides (Burbulys et al., 1991; Claverys and Håvarstein, 2007; Ellermeier et al., 2006; Engelberg-Kulka et al., 2006; Fawcett et al., 2000; González-Pastor et al., 2003; López et al., 2009; Molle et al., 2003). The B. subtilis cells that have not entered sporulation cycle are lysed (i.e., inactive Spo0A) (Fig. 3). There are reports suggesting that killer B. subtilis cells preferentially target non-B. subtilis cells, this indicates application of killer peptides as an antibiotic agent (Lin et al., 2001; Nandy et al., 2007). The killing factors are peptides that have been recently identified and evaluated against various human pathogens like methicillin-resistant S. aureus and S. epidermidis, an opportunistic pathogen (Liu et al., 2010). The potential advantages and disadvantages of killer factors are yet to be evaluated. 5. Antibacterial activities of non-antibiotic drugs Drugs in pharmacology are classified into antimicrobial agents and drugs for non-infectious disease (Williams, 1995). The drugs developed to treat non-infectious diseases but having antimicrobial activities are called non-antibiotics (Kristiansen, 1990) (Fig. 4). Effect of non-antibiotics on Gram positive bacteria, Gram negative bacteria, some fungal species, some viruses and protozoa had been demonstrated in several studies (Jones, 1996; Kristiansen, 1992; Kristiansen and Amaral, 1997; Molnar et al., 1992; Nicolau et al., 1995; Scheibel et al., 1987). Such antimicrobial properties have been reviewed for barbiturates, beta-adrenergic receptor antagonists, diuretic drugs, antihistamines, mucolytic agents, non-steroid anti-inflammatory drugs, proton pump inhibitors and psychotherapeutic drugs (Table 2) by Cederlund and Mardh, 1993. Although exact mechanism of action of these non-antibiotic drugs is not known but as they function on the level of plasma membrane like the case for sensitive eukaryotic cells, it can be hypothesized that they can function by altering cell permeability. Alternatively, they may function by affecting efflux pump of microbes, cross-membrane Fig. 3. Schematic representation of mechanism of Cannibalism in bacteria. In General conditions AbrB repressor remains bound to SdpABC operon and SdpRI operon preventing them to transcribe. But when nutrient depleted SpoA regulator get activated after its phosphoraylation and prevents further synthesis of AbrB repressor. As AbrB repressor removed both operons get activated. After activation, SdpRI operon produces SdpI immunity protein and Sdp ABC Operon produces SdpC toxin. This released SdpC toxin kills SpoA off cells resulting in release of nutrients in medium. SpoA on cells uptake these nutrients and delayed sporulation on the expense of their sister cells. SdpC toxin binds to SdpI immunity protein and provides self-protection to SpoA on cells. ions transport, cell energy transport, activity of membrane-bound enzymes (Tyski, 2003). Even though antimicrobial activity has been observed in non-antimicrobial drugs but the concentration at which they exhibits their activity is far more greater than physiologically observed. The combinatorial approach of nonantibiotic drugs with antibiotics may render susceptibility of antibiotic resistant bacteria to the concerned non-effective drug. A unification of -lactam antibiotics with phenothiazines to -lactam resistant micro-organism like Methicillin resistant S. aureus makes them sensitive. Some other combinations used are promazine and tetracycline, diclofenac and streptomycin, trimeprazine and sulfatiazole, chlorcyclizine and ciprofloxacin, chlorpromazine and erythromycin, propranolol and tobramycin (Tyski, 2003). Some scientist had called upon research community for development of phenothiazines like chlorpromazine, methdilazine and thioridazine as anti-tuberculosis drugs as these had been found to Please cite this article in press as: Nigam A, et al. Treatment of infectious disease: Beyond antibiotics. Microbiol Res (2014), http://dx.doi.org/10.1016/j.micres.2014.02.009 G Model MICRES-25661; No. of Pages 9 ARTICLE IN PRESS A. Nigam et al. / Microbiological Research xxx (2014) xxx–xxx 6 Fig. 4. The concept of non-antibiotics (Kristiansen, 1990). Chemical compounds that are used for medicinal purpose are classified as drugs. Drugs are further classified according to the medical treatment into antimicrobials/antibiotics (prokaryotic directed) for treatment of infectious disease and other drugs for treatment of non-infectious disease (eukaryotic directed). The concept of non-antibiotics came into existence when it was observed that many non-infectious drugs too have property of antimicrobials. These drugs are represented as non-antibiotics capable of affecting both prokaryotic and eukaryotic cells. be active against strains of M. tuberculosis both in vitro and in vivo (Amaral and Kristiansen, 2000). These drugs may act as lead compounds for rationalized drug discovery against pathogenic microbes. The prior information available on these drugs blended with the knowledge of their chemistry along with the tools of bioinformatics would ease the path of researchers. 5.1. Advantage and disadvantage The major advantage of application of non-antibiotic drugs is that their physiological impacts are well established. Their application as antibiotic involves three-dimensional approach. The first one is to remove its physiological impact and second one is to get rid of side effects both of which are well defined in literature. The third dimension involves an increment in the antibiotic activity of the non-antibiotic drugs (Cederlund and Mardh, 1993). The major bottleneck in their application is owing to the third dimension as most of these drugs display antibiotic activity at a concentration which is much higher to their physiological concentration aimed at treatment of non-infectious disease. Incrementing the activity of non-antibiotic drugs through rationalized drug discovery is the answer to this problem. type it is mediated through auto inducing signal detected through membrane receptor. The microorganism may possess either type of quorum sensing system or combination of both. The first type of quorum sensing is mainly mediated by acyl homoserine lactone (AHL) derivatives (Parsek et al., 1999) while auto inducing system involves peptides (Carnes et al., 2010). It was hypothesized that if this signalling system can be impaired the virulence of the microorganisms may be controlled without imposing selection pressure. As previously mentioned selection pressure results in evolution of drug resistant microbes (Fig. 5). This methodology that inhibits their proliferation without imposing selection pressure may be key to control evolution of drug resistant microbes (Dong et al., 2007). Quorum-quenching is mediated either through structural mimics of quorum-sensing molecules that compete with analogous quorum-sensing molecules or through inhibition of enzymes involved in synthesis of quorum sensing molecules, for example; the antibacterial Triclosan inhibits enoyl-ACP reductase which produces an important intermediate in AHL biosynthesis (Hoang and Schweizer, 1999). Another approach of quorum quenching involves enzymes such as AHL-lactonase and AHL-acylase respectively degrade quorum sensing molecules by hydrolysing the lactone ring or by liberating a free homo-serine lactone along with a fatty acid (Czajkowski and Jafra, 2009). 6. Quorum quenching 6.1. Advantage and disadvantage It was a generalized perception that microbes are unicellular entities that do not communicate among themselves. This perception was proven to be fallacy when quorum sensing was discovered. It was deciphered that microbial cells can communicate like cells of higher organism through messenger molecules. In many investigations it has been observed that microbial cell communication plays vital role in onset of virulence. Two mechanism of this cross talk have been recognized. First type of quorum sensing involves detection of signal through cytosolic transcription factor while in other Major advantage of using quorum sensing inhibitors is that it restricts evolution of drug resistant strain as it not enforces selection pressure. Both virulence and bio film formation require cell–cell communication via quorum sensing. Inhibition of the same enhances affectivity of antibiotics too; can be considered as an added advantage (Kalia, 2013). There appears to be no potential disadvantage related to application of quorum sensing inhibitors/enzymes in curbing infectious disease. Please cite this article in press as: Nigam A, et al. Treatment of infectious disease: Beyond antibiotics. Microbiol Res (2014), http://dx.doi.org/10.1016/j.micres.2014.02.009 G Model MICRES-25661; No. of Pages 9 ARTICLE IN PRESS A. Nigam et al. / Microbiological Research xxx (2014) xxx–xxx 7 Table 2 Antibiotic activity of some non-antibiotic drugs used in the treatment of non-infectious disease. The neuroleptic, H1 antihistamine and antidepressants drugs mentioned here possess similar structure. The information was summarized from the review of Cederlund and Mardh, 1993. Class Drugs Treatment/mechanism of action Antibiotic spectrum Reference -Adrenergic receptor antagonists Bupranolol S. aureus and E. coli Takahashi et al., 1983 -do- Propranolol Hypertension and glaucoma (Hoffman and Lefkowitz, 1990) -do- Himber et al., 1985 Diuretic drugs Amiloride Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa ˇ-Haemolytic group A streptococci, Enterococci -doBarbiturates Triamterene – -doE. coli Giunta et al., 1985 Gerber and Anton, 1974 Mucolytic agents N-acetylcysteine Parry and Neu, 1977 Anti-inflammatory (Non-steroid) Neuroleptic Sodium salicylate S. aureus, P. aeruginosa, K. pneumonia and Enterobacter cloacae Klebsiellapneumoniae Predominantly Gram-positive bacteria and some Gram-negative bacteria -doDisplay antibacterial activity Cederlund and Mardh, 1993 H. pylori Iwahi et al., 1991 H1 antihistamines Antidepressants Proton pump inhibitor Inhibitor of passive sodium influx and potassium excretion -doAnaesthetics and anticonvulsants Chronic bronchitis and cystic fibrosis Inflammation Phenothiazine/thioxanthene Fonazine/methdilazine/promethazine Amitriptyline/imipramine, nortriptyline/trimipramine Omeprazole/lansoprazole Duodenal/gastric ulcer Giunta et al., 1984, 1986 Domenico et al., 1989 -do-do- Fig. 5. Schematic representation of quorum quenching mechanism and a hypothetical way to decrease virulence. Las I protein synthesize a signalling molecule AHL (acyl homoserine lactone). This AHL molecule binds to las R resulting in activation of several virulence gene ultimately increasing cell density. Once this signalling system impaired it can control virulence of the microorganisms. 7. Conclusion The search for alternatives to antibiotics becomes more important considering increasing resistance of microbes towards antibiotics. Although the preliminary characterization of some of these alternatives in vitro has been known for long time but they were never exploited for their pharmaceutical properties. The research on phages as therapeutic agent needed to be revisited while research on bacteriocins needed to be taken more seriously. Further, greater efforts from biologists are required to identify and enhance the production of killing factors and quorum sensing molecules so that in vivo studies may be apprehended. The chemist can also play a vital role in the search of alternative to antibiotics by synthesizing bioactive molecules that are produced in tracer amounts in bioprocess. They may also contribute by reducing the non-antibacterial effect of ‘non-antibiotic antibiotics’ this may be followed by the investigation of the chemotherapeutic value of such antibiotics by biologist. Many drugs have often emerged from modifications in existing drugs which are better both in terms of reduced toxicity and high activity. Research focus on these alternatives is needed to be magnified with contribution from scientists from various disciplines for their application as therapeutic agents against infectious diseases. References Aasen IM, Markussen S, et al. 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