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“Non-Antibiotics- an Alternative for Microbial Resistance: Scope & Hope”

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4 Nonantibiotics – An Alternative for Microbial Resistance: Scope and Hope Debprasad Chattopadhyay, Soumen Kumar Das, Arup Ranjan Patra, and Sujit K. Bhattacharya

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Abstract
The antimicrobial activity of nonchemotherapeutic compounds, such as methylene blue, phenothiazine, thioxanthene and related agents, has been known since the time of Paul Ehrlich (1854–1915). In this context the term ‘nonantibiotics’ was introduced to include a variety of compounds used in the management of pathological conditions of noninfectious etiology. Despite the availability of hundreds of anti-infective drugs the emergence of ‘antibiotic resistance’ and new infectious agents creates the therapeutic challenge to the medical community. Hence, the search for newer agents to tackle the global problem is continuing. It has been noted that many of the phenothiazines, thioxanthenes, other neurotropics, antihistamines, anesthetics, analgesics, antihypertensives, muscle relaxants, some cardiovascular agents and so on can inhibit diverse classes of microbes, as well as the drug-resistant strains at different dose levels, by modifying the architecture of the microbial membrane and its permeability. A review of the literature suggests that some of these membrane-active compounds can enhance the activity of conventional antibiotics, eliminate natural resistance to specific antibiotics (reversal of resistance) and exhibit strong activity against multidrug-resistant forms of Staphylococcus aureus, Escherichia coli, Salmonella spp., Mycobacterium tuberculosis, Plasmodium falciparum and so on. This chapter covers the antimicrobial activity of some nonantibiotics, especially against drug-resistant microbes, that cause therapeutic challenge with an emphasis on the group of drugs used as antihistamines, sedatives, hypnotics and so on, and their stereoisomers.

4.1 Introduction

Antibiotics are substances produced by microorganisms that can destroy or inhibit the growth of other microorganisms and can even act against some cancer cells. On the

New Strategies Combating Bacterial Infection. Edited by Iqbal Ahmad and Farrukh Aqil Copyright Ó 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32206-0

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j 4 Nonantibiotics – An Alternative for Microbial Resistance: Scope and Hope other hand, substances of nonmicrobial origin that have similar effects on microbes or malignant cells are described as chemotherapeutic agents [1]. Drugs that are neither antibiotics nor antimicrobial chemotherapeutic agents, but which possess antimicrobial properties, are termed ‘nonantibiotics’ [2]. Pharmacologically, drugs have been classified on the basis of their apparently major and predominant pharmacological action, such as antihistamines, analgesics, antihypertensives, neuroleptics, local anesthetics, anti-inflammatory agents and so on. Nevertheless many of the drugs are basically multifunctional and show different activity at different dose levels [3]. This multiplicity of function, other than their first described one, may be quite significant. Hence, redescriptions of such drugs are possible (e.g. Prontosil, an azo dye containing a sulfonamide group, was later developed as an antibacterial agent) [4, 5]. Similarly, the synthetic nitrofurantoin is a selective antibacterial against urinary tract bacteria, but can also damage mammalian DNA [6]. Likewise, the phenazine dye clofazamine possesses antihistaminic, anti-inflammatory as well as powerful antibacterial action against leprosy bacilli by inhibiting DNA template formation [7]. Similarly, the traditional analgesic aspirin (acetyl salicylic acid) is now often prescribed as an anticoagulant for cardiovascular diseases [8]. Metronidazole, a nitroimidazole, is a powerful broadspectrum amebicide as well as a DNA degrader in obligate anaerobic bacteria [9], while cyproheptidine (periactin) is an antihistamine as well as an anabolic stimulant [10]. Hence, the term ‘nonantibiotics’ is considered to include a variety of compounds like antihistamines, anesthetics, hypnotics, sedatives, antipsychotics, analgesics, diuretics, antihypertensives, muscle relaxants, cardiovascular agents and many more which are used in the management of pathological conditions of a noninfectious etiology, but can modify the cellular permeability of microbes and exhibit broad-spectrum antimicrobial activity. The antimicrobial properties of several nonantibiotic compounds have been investigated sporadically and their application for the management of microbial infections has not been systematically evaluated. It has been reported that a variety of ‘nonantibiotic’ compounds used in the management of noninfectious etiology have broad-spectrum antimicrobial activity against viruses [11–16], Mycoplasma [17, 18], bacteria [19–74], Mycobacteria [7, 75–92], yeast [93–95], protozoa such as Amoeba [96–97], Plasmodium [98–101], Leishmania [102–107], Trypanosoma [108–110] and helminths [111] both in vitro and in vivo [2, 3, 19, 23, 26, 41, 49, 51, 53, 56, 61, 67–69, 71–74, 77, 82–89, 91, 105, 108, 109]. Many of these nonantibiotics can modify the cellular permeability of the microbes [2, 3, 18–20, 23, 25, 27, 30, 34, 38–40, 46, 54, 59, 60, 79, 81, 95, 101–103, 107, 112]. This chapter will present the antimicrobial activity of some potential ‘nonantibiotics’ especially against drug-resistant microbes like viruses, bacteria, fungi and protozoa, with an emphasis on the psychotherapeutic, antihistaminic, sedative and hypnotic agents, and their stereoisomers.

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4.2 Historical Development: Nonantibiotics with Antimicrobial Potential

The antimicrobial activity of synthetic, nonchemotherapeutic compounds, such as methylene blue, phenothiazines and so on, has been known since the time of Paul

4.2 Historical Development: Nonantibiotics with Antimicrobial Potential 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 Figure 4.2 Phenothiazines. Figure 4.1 Methylene blue.

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Ehrlich (1854–1915). During the second half of the nineteenth century aniline dye was extracted from coal tar in the dyeing industry [113], but in 1876 the German dye-stuff expert Heinrich Caro extracted methylene blue from aniline, while in 1883 methylene blue was synthesized as a derivative of phenothiazine [114]. Methylene blue (Figure 4.1) was first used by Paul Ehrlich as a bacteriological stain, and he discovered that methylene blue and its analogs had pronounced affinity for nerve and brain tissue [115]. Later, Ehrlich applied methylene blue in the treatment of neuritic and rheumatic pain [116], and in 1891 he used this dye in the treatment of malaria [117]. Simultaneously, the Italian physician Pietro Bodoni discovered that methylene blue had a positive effect on psychotic patients [118]. In 1939 it was found that sterile urine from rabbits fed with phenothiazine (Figure 4.2) remained sterile for several weeks even when exposed to air, which led to the therapeutic trial of phenothiazine in urinary tract infections [21] with positive results. Interestingly, it was observed that suture material prepared from the gut of phenothiazine-treated sheep was more stable and stronger than the known material. Hence, phenothiazines were used by veterinarians in the treatment of intestinal parasites, especially as antihelminthics [111]. However, the interest in phenothiazines as antimicrobial candidates declined with the discovery of penicillin by Alexander Fleming in 1928 [119] and, later, a number of ‘classic’ antibiotics like streptomycin [120]. However, after World War II the French military surgeon Henri Marie Laborit discovered that phenothiazines could be used in the therapy of shock and pain after surgery as analgesics [121], thus confirming the initial observation made by Ehrlich and Leppmann in 1890 with methylene blue [116]. Laborit [121] also found that phenothiazines had a calming effect on patients and proposed that these agents might be used as sedatives in psychiatric treatment. However, in the context of emerging microbial diseases like severe acute respiratory syndrome, human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome, and re-emerging diseases like tuberculosis and malaria as well as

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j 4 Nonantibiotics – An Alternative for Microbial Resistance: Scope and Hope drug-resistant microbes create a therapeutic challenge to the clinicians which needs more new and improved drugs. To counter the challenge of microbial resistance, drug companies and scientific community are expanding work on new antibiotics, as well as modifications of the naturally occurring antibiotics that exhibit little or no toxicity to humans [120]. The alarming worldwide increase in the frequency of antibiotic resistance [120, 122] suggests that more antibiotics are needed for the initial or adjuvant management of patients with infections caused by high-frequency multidrug-resistant (MDR) pathogens. There is evidence that certain nonantibiotic compounds, alone or in combination with conventional antibiotics, may play a useful role in the management of specific bacterial infections associated with a high risk of resistance to conventional antibiotics [2, 3, 18, 48, 53, 56, 64, 83, 84, 86–88, 92, 123–128]. A review of the literature, coupled with some recent investigations, suggests that some of these and other membrane-active compounds enhance the activity of conventional antibiotics or chemotherapeutic agents [2, 18, 25, 56, 64, 65, 74, 77, 84, 86, 89– 92, 123, 125, 126, 128–140], eliminate natural resistance to specific antibiotics (reversal of resistance) and exhibit strong activity against multi-drug resistant strains of Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Streptococcus pneumoniae, Escherichia coli, Enterococcus faecalis, Burkholderia pseudomallei, Mycobacterium tuberculosis and Plasmodium falciparum [141–156]. Thus nonantibiotics may have a significant role in the management of certain bacterial infections and a list of some well-studied nonantibiotics with their antimicrobial activity against microbes is presented in Table 4.1.

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4.3 Psychotherapeutics as Nonantibiotics

Out of different categories of drugs, psychotherapeutics have long-standing antimicrobial potential. The major group of psychotherapeutic drugs includes phenothiazines, thioxanthenes and phenylpiperidines. ‘Phenothiazines’ [10H-phenothiazine, C12H9NS; (Figure 4.2)], developed as synthetic dyes in 1883, are the largest of the five main classes of neuroleptic antipsychotics. Chemically, phenothiazines are dibenzothiazine or thiodiphenylamine with a three-ring structure in which two benzene rings are joined by sulfur and nitrogen atoms at nonadjacent positions, obtained by fusing diphenylamine with sulfur. Phenothiazine is a semivolatile organic compound used as an intermediate of various antipsychotic neuroleptic drugs [157], introduced as an insecticide by DuPont in 1935, and as an antihelminthic in livestock and for the manufacture of rubber additives [158]. Phenothiazine pesticides work by affecting the nervous system of insects, inhibiting the acetylcholine breakdown by blocking the enzyme acetylcholinesterase and is a potent a-adrenergic blocker. Hence, many of their side-effects are due to their anticholinergic blocking effects [159]. Chlorpromazine (Figure 4.3) was the first neuroleptics used in psychiatry [160]. The structure–activity relationship study revealed that stereoisomerism is responsible for the antimicrobial activity of optically inactive chlorpromazine (Figure 4.3) and

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45 Compounds methylene blue (aniline) Activity against Reference dimethyl methylene blue phenothiazine [1, 101] [152] [54] [171] [13] [17] [79] [76, 78, 86] [156, 181] [86] [87] [95] [97, 96] [111] [108, 109] [21] [43] [50, 59] chlorpromazine Plasmodium falciparum Plasmodium vinckei petteri, Plasmodium yoeli nigeriensis Helicobacter pylori DNA and RNA virus Mycoplasma spp. Mycobacteria (slow growing) Mycobacterium tuberculosis Mycobacteria (Isoniazid) Mycobacteria spp. Mycobacteria (MDR) Yeast Amoeba proteus Helminthes Trypanosoma, Leishmania spp. Escherichia coli (UTI) intestinal anaerobes Bacteroides spp., Prevotella spp., Fusobacterium spp., Vibrio cholerae, Plasmodium falciparum, Leishmania spp., Candida spp., Amoeba spp. plasmid replication Mycobacterium tuberculosis (4–12 mg/ml)a influenza virus bacteria (5–10 mg/ml)a [43] [25, 77–79, 83, 87, 173] [11] [22, 31] (Continued) 4.3 Psychotherapeutics as Nonantibiotics

Table 4.1 Antimicrobial activity of some important nonantibiotics.

Class

Dyes

Antipsychotic (Aliphatic)

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Table 4.1 (Continued)

Class

(Piperazines) (Piperadines)

j 4 Nonantibiotics – An Alternative for Microbial Resistance: Scope and Hope

Antihistaminic

(Ethanolamine)

(Alkyl amine)

44 Compounds Activity against Reference [47] [40] [93, 94] [102, 103, 106] [105] [31] [98] [78, 70] [70] [47] [100] [88, 156] [90] [62] [50] [51, 61, 133, 134] promazine triflupromazine levomepromazine prochlorpromazine thioridazine tricyclic antipsychotics alimemazine methdilazine promethazine phenergan bromodiphenhydramine Escherichia coli, Vibrio cholerae, Salmonella typhimurium Bordetella spp. Candida spp. Leishmania donovani Staphylococcus aureus, Enterococcus faecalis, R factor elimination Plasmodium falciparum Mycobacterium tuberculosis (10 mg/ml) antimicrobial antibacterial antibacterial Plasmodium falciparum Mycobacterium tuberculosis (10)a Mycobacterium tuberculosis (6–32)a Mycobacterium avium Proteus vulgaris bacteria (37)a Staphylococcus aureus, Escherichia coli, Shigella spp., Salmonella spp., Klebsiella, Proteus spp., Pseudomonas aeruginosa Mycobacterium tuberculosis (5–15)a Trypanosoma spp., Escherichia coli adhesion Mycobacterium tuberculosis Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Klebsiella spp., Pseudomonas spp., Mycobacterium spp. bacteria [82] [41, 110] [75] [32] diphenhydramine clofizamine [33, 80]

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45 tripolidine femoxetine paroxetine cyproheptadine [154] [120] [63] [47, 79] prochlorperazine trifluoperazine dye, steroid bacteria enterobacteria (

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