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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).
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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
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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.
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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
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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
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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
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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.
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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.
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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