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Antimicrobial Resistance Review

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For more than 50 years, the human society routinely used antimicrobials for treatment and prophylaxis of infectious diseases caused by pathogenic microorganism. Although Antibiotics have saved large number of lives and an essential part of modern medicine, they have been responsible for evolutionary stress on bacterial population and the emergence of antimicrobial resistant mutants among the bacteria, which has decreased efficacy and withdrawal of the antimicrobial from the clinical practice [Coates and Hu, 2011]. Antimicrobial resistance (AMR) is known as one of the greatest challenge of the twenty-first century to human health in the world [IDSA, 2011]. AMR has a great impact world economy with the loss of labor force and increased load on health service, which will reduce the national outputs of most countries. One of the factors contributing to the cause of the AMR crisis are the increasingly interconnected human population, the ablity of the microbes to adapt to environmental challenges and the over prescription of antimicrobials agent by health professionals [Michael et al., 2014].

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Antimicrobial resistance infections and related morbidity and mortality, clearly highlights the urgent need for new and improved antimicrobial drugs has resulted significant research efforts, with new compounds with new mode of action for use in clinical practice[IDSA., 2010]. Unfortunately, after more than half a century the success of the pharmaceutical industry is now producing too few antimicrobial agents, to replace antibiotics that are no longer effective for many types of infection because antimicrobial drug development and research is risky, scientifically more complex, and expensive but too little potential profit, and time consuming [Projan, 2003]. Until now, pharmaceutical industry has been coping with this problem by modifying the existing antibiotics and developing new ones. But, only few groups of antibiotics [i.e.oxazolidinones, lipopeptides, pleuromutilins, tiacumicins, diarylquinolines and streptogramins] have been marketed in the last four decades and all of them are for the treatment of gram positive bacterial infections [Pelaez F., 2006, Coates et al., 2011].

A broader approach is needed to solve the problem of multi drug resistant bacterial infection. One of the main approaches in the industry is adopting the identification, validation and exploitation of new targets to identify and develop novel antibiotics that will be active against resistant micro organisms. Although there are a large number of antibiotics used clinically, the variety of targets that they inhibit is limited [McDevitt et al., 2002]. The analysis of microbial genomes has revealed an abundance of novel and potentially essential targets and help to access to uncultivable microorganisms via screening gene products found by expressing genes recovered directly from the environment. This bypasses culturing process of the microorganism [Payne et al., 2001]. Because 99% of microorganisms are proposed to be unculturable, this approach significantly deepens the pool for source organisms. Developing new antimicrobial agent that acts on non-multiplying bacteria is another important approach that may lead to drugs that decrease the emergency of antimicrobial drug resistance and improve patient compliance by shortening the duration of antimicrobial treatment. For the time being, the most new antibiotics that approved for clinical practice screened in a conventional way against live multiplying bacteria [ Coates et al.,2011, McDevitt et al., 2002].

The ability of newer, directed-spectrum antibiotics to circumvent multidrug-resistance mechanisms are the result of their novel mechanisms of action. Thus, these antibiotics provide a fresh face in antimicrobial chemotherapy and an invaluable tool in the fight to prevent overwhelming antibiotic-resistance issues. The ability of antibiotics to safely cure infections depends on their exploitation of the differences between the biochemical pathways in bacteria and human cells. Targets for antimicrobial drug discovery can be chosen rationally on the basis of such differences [Payne et al., 2001, Yuan et al., 2001].The objective of this review was to find out various promising novel antimicrobial targets and alternatives ways to antimicrobial agent approaches is described.

Virulence factor inhibitors

Virulence factors are substances synthesized by bacteria that causes and determine the severity of disease. Once the infection takes place in the host these microbes rapidly activate the target genome and produce virulence factors that help the them to invade the host, initiate the infection and facilitate colonization and evade host defense system [Rasko and Sperandio , 2010]. These virulence factors are adherence Factor, Invasion Factors, polysaccharide capsules, lipopolysaccharide endotoxin , Toxins and Siderophores [Rasko and Sperandio , 2010, Cegelski et al., 2008]. A new strategy for the management of bacterial infections involves inhibiting the expression of these virulence factors, without killing the bacteria which causes less evolutionary pressure for the emergency of resistant genes, makes the bacteria less prone to invade the host and interrupt infection progression. Among the main anti-virulence strategies are inhibition of, quorum-sensing compound, toxin, bacterial adhesion to the host cell and organism-specific virulence gene expression [Cegelski et al., 2008].

Anti toxins

Toxins are antigens secreted by microbes to act on the host tissue and can stimulate specific antibodies called antitoxins [Goeders and Van, 2014]. Antimicrobial monoclonal antibodies (mAbs) synthesized by the host against microbial cell surface targets and soluble exotoxins. Its mode of action depends on the nature of the target, its role in the pathogenesis, isotype and structure. Anti-exotoxin mAbs attenuate microbial pathological effect by different modes including exotoxin neutralization, antibody-dependent phagocytosis, complement-mediated bactericidal activity and immune system-independent microbial killing [DiGiandomenico and Sellman., 2015].

Antimicrobial mAbs act by neutralization of exotoxins by binding to soluble exotoxins which leads to the formation of antibody-toxin complexes, which are mainly cleared by the reticuloendothelial system. All the clinically used antimicrobial mAbs act via toxin neutralization. Neutralizing efficacy of mAbs directly correlated with mAb binding affinity [Oleksiewicz et al., 2012]. Raxibacumab is the leading biologic product that has an anti-protective antigen [PA] mAb, uesd for the management of anthrax in combination with antimicrobial agents. It binds free PA and inhibits engagement of PA to its receptors on macrophages. The antibody inhibits the entry of anthrax edema and lethal factor in to the host cell, which contribute substantially to the pathogenic effects of anthrax toxin [Jurado et al., 2008].

Obiltoxaximab is also another anti-PA mAb that was approved to prevent against anthrax toxin through inhibition of PA binding to cellular receptors on host cells. It is a chimeric agent, with 50-fold increase in affinity and neutralizing ability [Rodgers and Chou, 2016]. Bezlotoxumab is a human IgG1 used to reduce recurrence of Clostridium difficile infection [CDI] who are receiving antimicrobial agents for CDI and are at high risk for CDI recurrence. It binds with high affinity to toxin B, a vital virulence factor and inhibits toxin B binding to host cell. Hence it prevents toxin B-mediated inactivation of Rho GTPases and downstream signaling cascades in cells. [Wilcox et al., 2017]. In addition to the above agents, currently there are many mAbs are in clinical trials. Among these six mAbs are developed against S.aureus [514G3, MEDI4893, Salvecin [AR-301], DSTA-46375, Suvratoxumab, ASN-100] two are targeting Pseudomunosa aeruginosa [MEDI-3902A, Aerubumab] and two is for E. coli [PolyCab, MM-529 ] [Czaplewski et al.,2016].

The antibody also helps the uptake of antibiotic into phagolysosomes, where this antibody–antibiotic conjugate activated only when it is released in the proteolytic situation of the phagolysosome, allowing effective activity against intracellular bacteria. This strategy showed promising bactericidal activity against vancomycin-resistant S. aureus [Lehar et al., 2015]. Antibody-antibiotic conjugates proposed to be favorable pharmacokinetics [i.e., increases half-lives] decreases toxicity [Sause et al., 2016., Dadachova et al., 2004].

mAbs also may facilitate the removal of bacteria from the body by stimulating the host immune system. Studies showed the benefit of anti- Programmed death [PD]-1 mAb for the management of tuberculosis infection. PD-1 and its ligands decreased in CD4+ and CD8+ T cells in TB patients after standard-of-care therapy. Management with anti-PD-1 mAb restored cytokine secretion and antigen responsiveness of T cells isolated from TB patients ex vivo [Jurado et al., 2008, Topalian et al., 2012].

Biofilm formation inhibitor

Bacteria combine to create adherent agglomerates known as biofilms that causes two thirds of infections. Biofilm helps the microbes to survive in harsh condition and enhance their resistance to drug by 1000-fold.The reason is due to the mucoid nature of biofilm which defend them from antibacterial agent exposure, the metabolic state of bacteria in nutrient depleted condition in the biofilm may lead to dormancy which makes them resistant to drugs since they grow slowly, biofilm cells have a higher rate of mutation [Simões et al., 2010]. In addition biofilm defend the microbes from the host immune system by inhibiting activation of phagocytes and complement system. As a result treatment usually fails to clear biofilm from infection site because of their higher values of minimum bactericidal concentration and minimum inhibitory concentration, which may result in in-vivo toxicity [Simões et al., 2010, Anderson et al., 2003].

Biofilm formation begins as the bacteria adhere to a substrate followed by micro colonies formation and finally differentiation of biofilm into a mature structure. Then these microbes start secreting extracellular polysaccharide substance, until ensuring the safe attachment to the surface in a thickly complex bio-molecular layer. Since biofilm formation has contribute in bacterial pathogenicity and emergency of resistance to antibiotics, screening of new anti-biofilm agents with novel targets and mode of action is important. [Anderson et al., 2003, Waters et al., 2008]. Nitric oxide [NO], a signaling compound, implicated in biofilm dispersal. Thus, the exogenous addition of non-toxic amount of NO stimulates phosphodiesterases that degrade c-di-GMP, a vital regulator of biofilm formation and dispersal, thus triggering a switch to a planktonic phenotype [Barraud et al., 2006]. Synthetic cationic peptides, derived from natural peptides including human cathelicidin LL-37 and the bovine peptide indolicidin inhibit biofilm formation. Cationic antimicrobial Peptide 1018 also a potent broad-spectrum anti-biofilm activity that bind and facilitate degradation of guanosine 5′-diphosphate 3′-diphosphate [[p]ppGpp] nucleotides, a signal in biofilm formation and maintenance [Dürr et al.,2006].

Teichoic acids Inhibitors

Teichoic acids targets are promising antimicrobial targets, due their essential roles in bacterial viability in vitro, in immune evasion, during cell division, in resistance to host defenses and antibiotics and have no human homologs. Because of their diverse roles, inhibition of different steps of teichoic acids biosynthesis can result in different phenotypes. Recent studies has demonstrated that deleting or inhibiting Teichoic acids synthesis resensitizes methicillin-resistant S. aureus to β-lactams antibiotics [Pasquina et al.,2013]. There are antibiotic targets in the Teichoic acids synthesis pathway since Teichoic acids essentiality is due to accumulation of toxic intermediates and depletion of the undecaprenol-phosphate lipid carrier, which is also used for Prostaglandin synthesis. Chemical agents that block these essential targets prevent bacterial growth. Rapid progress has been made toward developing an agent to validate Teichoic acids s as good antimicrobial targets. The first targets were in the D-alanylation pathway, but Teichoic acids inhibitors have since been developed and several natural product derivatives are suggested to disrupt LTAs [Farha et al.,2012].

Quorum Sensor synthesis inhibitor

Bacteria synthesize signaling substances called autoinducers, which help the bacteria to estimate their number. When the amount of these signaling substances is too low, bacteria simply proliferate to increase their number. The amount of those signaling substances increases parallel to their mass. When a threshold mass is achieved, the bacterial virulence increases or biofilm formation and auto-inducing their synthesis occurs. This phenomenon is called quorum sensing (QS) [Redfield, 2002]. In addition, QS controlled gene expression help for biofilm formation and drug resistance [Miller and Bassler , 2001]. So, QS is a promising new target for a new group of antibacterial agent which would prevent activation of QS signals substances in vivo, and thereby be capable of decreasing the pathogenesis of bacteria. As QS does not directly contribute in the growth of bacteria, so blocking effects of QS substances does not impose selective pressure for emergency of resistance as with antibiotics [Redfield et al., 2002, Clatworthyet al., 2007].QS inhibition, also known as quorum quenching, can be achieved by blocking the receptors with antagonistic agents, by interfering autoinducer synthesis and signal propagation or by degrading the autoinducers by hydrolytic enzymes. These approaches then lead to a reduction in biofilm formation [Clatworthy et al., 2007].

AHL synthesis inhibitor

In most bacteria QS system activities done by biosynthesis of signal substance in the form of acylhomoserine lactones [autoinducers]. QS System can be inhibited by blocking the synthesis of N-acylated homoserine lactone[AHL] by an AHL synthase enzyme. Even through some substrate analogues, including holo-ACP, L/D-S-adenosylhomocysteine, sinefungin and butyryl-S-adenosylmethionine [butyryl-SAM], can block AHL synthesis in vitro. How these analogues of the AHL building blocks, SAM and acyl-ACP, which are also used in central amino acid and fatty acid catabolism, would affect other cellular functions is presently unknown [Redfield , 2oo2, Geske et al., 2005].

Inactivation of signal molecules

Inactivation of QS signal substance can be done by using chemical breakdown, enzymic degradation and metabolism of the AHL. Large number of enzymes can distract the bacterial QS signal substance identified like A-HSL-lactonases, A-HSL- acylases and paraoxonases. Their mode of action are the break down of the lactone ring by the lactonases, disruption of the acylated chain by the acylases and breakdown of the lactone ring by the paraoxonases [Dong and Zhang , 2005, Dobretsov et al.,2009].

QS Signal receptor inhibitor

Most widely used method is to block the QS signal receptor with an analogue of the AHL signal molecule. There are many Synthetic receptor blockers with an analogue of the AHL signal substance [Rasmussen and Givskov , 2006]. Although QS signal receptor blocker work well in vitro it is a pretty long shot to claim that it will attenuate virulence in vivo scenarios. A simple model to demonstrate the virulence of P. aeruginosa is in a Caenorhabditis elegans. These nematode worms feed harmless bacteria, but when they graze on a lawn of P. aeruginosa rapidly die. The reasons in the death of the worm are due to the synthesis of HCN and phenazines, both of which are QS controlled. A 100% killing of the worms is occurring rapidly when the worms feed on wild-type P. aeruginosa. When the worms feed on P. aeruginosa QS knockout mutants, the killing is reduced to 10 %, indicating QS systems are required for the expression of full virulence. The mortality of worms fed wild-type P. aeruginosa with garlic extract was reduced to 40% and 5%.

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