367
with an estimated two million deaths every year (WHO 2015). The five commonly
used anti-TB drugs are rifampicin, isoniazid, ethambutol, pyrazinamide and streptomycin (WHO 2013). Resistance to all these anti-TB drugs has been reported over
time. Latest estimate puts the multidrug-resistant (MDR) TB burden to be at an
estimated 0.48 million, among which around 9% are extensively drug-resistant
(XDR) TB cases (WHO 2015). The only new anti-TB drug approved in the last 40
years
is
bedaquiline
(http://www.accessdata.
fda.gov/drugsatfda_docs/
label/2012/204384s000lbl.pdf) with an FDA approval for its use only in MDR and
XDR patients.
The sturdy multilayered cell wall of Mycobacterium consists of an inner peptidoglycan layer, surrounded by a layer of mycolic acid linked to arabinogalactan and
the outermost layer of glycolipids and lipoglycans (Brennan 2003). This unique
nature of mycobacterial cell makes it impenetrable to most common surfactants and
antibacterial agents. The ability of bacteria to thrive in acidic pH inside the macrophage gives mycobacteria additional survival advantages. Mycobacteria have
recently been shown to produce biofilms (Ojha et al. 2008). Thus in addition to
resistance toward existing drugs, all the aforementioned factors make a compelling
case for accelerated research to identify novel antimycobacterial candidates. One
such area of drug discovery research with high potential is antimicrobial peptides.
AMPs have low immunogenicity and a wide range of activity, thus making them
desirable antimicrobial candidates. A wide range of peptides are derived from all
life forms with target sites ranging from the cell membrane to intracellular sites. In
this chapter, we will discuss the origin, synthesis and isolation techniques of various
antimycobacterial peptides as well as their mechanism of action.
15.2 Cell Membrane Inhibitors
15.2.1 E50-52A
Bacteriocins are cationic antimicrobial peptides produced by bacteria that are ribosomally synthesized and can permeate membranes (Cotter et al. 2005). E50–52A is
a class IIa bacteriocin isolated from Enterococcus faecalis (Sosunov et al. 2007). It
has a molecular weight of ~4 kDa and an isoelectric point of 8.0. The antimicrobial
activity of E50–52A ranges from the inhibition of genus Campylobacter, Yersinia,
Escherichia and Salmonella. Its inhibition of M. tuberculosis H37Rv is at par with
rifampicin. The major drawback with the use of E50–52 peptide is its cytotoxicity
at higher levels as well as its inability to penetrate the host membrane at physiologically tolerable concentrations. In a macrophage model of infection, the peptide was
conjugated with phosphatidylcholine–cardiolipin. This E50–liposome complex
could enter macrophages and contain mycobacterial growth without lysis of macrophages. Similarly, in a mouse model of acute TB infection, E50–liposome complex
inhibited mycobacterial growth in vivo and increased the lifespan of infected mice
(Sosunov et al. 2007).
15 Antimycobacterial Peptides
with an estimated two million deaths every year (WHO 2015). The five commonly
used anti-TB drugs are rifampicin, isoniazid, ethambutol, pyrazinamide and streptomycin (WHO 2013). Resistance to all these anti-TB drugs has been reported over
time. Latest estimate puts the multidrug-resistant (MDR) TB burden to be at an
estimated 0.48 million, among which around 9% are extensively drug-resistant
(XDR) TB cases (WHO 2015). The only new anti-TB drug approved in the last 40
years
is
bedaquiline
(http://www.accessdata.
fda.gov/drugsatfda_docs/
label/2012/204384s000lbl.pdf) with an FDA approval for its use only in MDR and
XDR patients.
The sturdy multilayered cell wall of Mycobacterium consists of an inner peptidoglycan layer, surrounded by a layer of mycolic acid linked to arabinogalactan and
the outermost layer of glycolipids and lipoglycans (Brennan 2003). This unique
nature of mycobacterial cell makes it impenetrable to most common surfactants and
antibacterial agents. The ability of bacteria to thrive in acidic pH inside the macrophage gives mycobacteria additional survival advantages. Mycobacteria have
recently been shown to produce biofilms (Ojha et al. 2008). Thus in addition to
resistance toward existing drugs, all the aforementioned factors make a compelling
case for accelerated research to identify novel antimycobacterial candidates. One
such area of drug discovery research with high potential is antimicrobial peptides.
AMPs have low immunogenicity and a wide range of activity, thus making them
desirable antimicrobial candidates. A wide range of peptides are derived from all
life forms with target sites ranging from the cell membrane to intracellular sites. In
this chapter, we will discuss the origin, synthesis and isolation techniques of various
antimycobacterial peptides as well as their mechanism of action.
15.2 Cell Membrane Inhibitors
15.2.1 E50-52A
Bacteriocins are cationic antimicrobial peptides produced by bacteria that are ribosomally synthesized and can permeate membranes (Cotter et al. 2005). E50–52A is
a class IIa bacteriocin isolated from Enterococcus faecalis (Sosunov et al. 2007). It
has a molecular weight of ~4 kDa and an isoelectric point of 8.0. The antimicrobial
activity of E50–52A ranges from the inhibition of genus Campylobacter, Yersinia,
Escherichia and Salmonella. Its inhibition of M. tuberculosis H37Rv is at par with
rifampicin. The major drawback with the use of E50–52 peptide is its cytotoxicity
at higher levels as well as its inability to penetrate the host membrane at physiologically tolerable concentrations. In a macrophage model of infection, the peptide was
conjugated with phosphatidylcholine–cardiolipin. This E50–liposome complex
could enter macrophages and contain mycobacterial growth without lysis of macrophages. Similarly, in a mouse model of acute TB infection, E50–liposome complex
inhibited mycobacterial growth in vivo and increased the lifespan of infected mice
(Sosunov et al. 2007).
15 Antimycobacterial Peptides