14
ated, etc. (Gootz 2010). These pathogens also have the dexterity to communicate
with each other by the process of “quorum sensing” where the process of cell-tocell signaling is under the control of “autoinducers” which are classified as signaling molecules. Quorum sensing regulates the expression of virulence gene and the
traits that are involved in biofilm formation, thus making the pathogen more resistant toward antibiotic attack. The severity of antimicrobial resistance catches the
attention of the World Health Organization (WHO) which is drafting the global
action plan on the problem of antimicrobial resistance and the ways to combat this
crisis (WHO 2014). Various national and international agencies are striving to promote awareness on the problem, rational use of antibiotics, measures for controlling outbreaks, and design of new antibiotics or adjuvant therapeutics which can
increase the sensitivity of known antibiotics/antimicrobials (White House
Executive Order 2014; Chaudhary 2016).
One feasible strategy to overcome antimicrobial resistance is to target the physiological pathways responsible for acquisition of essential microbial nutrients
(Clatworthy et al. 2007). Iron is a vital micronutrient for virtually all forms of life
where its main role is to act as cofactor of key enzymes which plays a role in
energy generation, DNA replication, RNA synthesis and other cellular processes,
etc. and ultimately responsible for the survival of microorganism (Skaar 2010).
Thus, acquiring iron is crucial for the sustainability of pathogen inside the host. It
is well documented that pathogen depends on host machinery for the requirement
of iron and during inflammation and febrile conditions, the sequestration of iron
and other micronutrients from the pathogen provides “nutritional immunity” to the
host (Vasil and Ochsner 1999). Limiting the iron requirement to pathogens interferes with its metabolic processes and thus inhibits their growth. In contrast,
microbial pathogens, viz., bacteria and fungi, have evolved with the complex system to uptake iron from host, including hemoproteins, other iron-binding proteins
(transferrin), and iron chelators called “siderophores” (Cornelis and Matthijs
2002). These are low molecular weight (< 1 kDa) compounds which have strong
affinity for iron; their complexes with iron serve as a means of transport of iron
across the cell membranes. These diverse compounds have great structural and
functional properties (Renshaw et al. 2002).
These “iron carriers” are produced and secreted by bacteria, fungi, and monocotyledons plants under the condition of low iron stress and, thus, serve as carrier for uptaking iron for pathogenic microbes from the host environment.
Figure 2.1 depicts the pathway of uptake of iron (III) by hydroxamate-based
fungal siderophores of Aspergillus fumigates (Moore 2013). The fungal cell wall
is made of chitin and glucan and allows limited permeability of nutrients to periplasmic space and plasma membrane (Farkas 1985). However, this permeability
keeps on altering during different phases of growth. During iron-deficient conditions, the siderophores are released into the external environment and form complex with iron (III) form. This complex is well recognized by membrane proteins
which facilitate the transport of bulky iron-siderophore complex across the cell
S. Bhatia and S. Singh
ated, etc. (Gootz 2010). These pathogens also have the dexterity to communicate
with each other by the process of “quorum sensing” where the process of cell-tocell signaling is under the control of “autoinducers” which are classified as signaling molecules. Quorum sensing regulates the expression of virulence gene and the
traits that are involved in biofilm formation, thus making the pathogen more resistant toward antibiotic attack. The severity of antimicrobial resistance catches the
attention of the World Health Organization (WHO) which is drafting the global
action plan on the problem of antimicrobial resistance and the ways to combat this
crisis (WHO 2014). Various national and international agencies are striving to promote awareness on the problem, rational use of antibiotics, measures for controlling outbreaks, and design of new antibiotics or adjuvant therapeutics which can
increase the sensitivity of known antibiotics/antimicrobials (White House
Executive Order 2014; Chaudhary 2016).
One feasible strategy to overcome antimicrobial resistance is to target the physiological pathways responsible for acquisition of essential microbial nutrients
(Clatworthy et al. 2007). Iron is a vital micronutrient for virtually all forms of life
where its main role is to act as cofactor of key enzymes which plays a role in
energy generation, DNA replication, RNA synthesis and other cellular processes,
etc. and ultimately responsible for the survival of microorganism (Skaar 2010).
Thus, acquiring iron is crucial for the sustainability of pathogen inside the host. It
is well documented that pathogen depends on host machinery for the requirement
of iron and during inflammation and febrile conditions, the sequestration of iron
and other micronutrients from the pathogen provides “nutritional immunity” to the
host (Vasil and Ochsner 1999). Limiting the iron requirement to pathogens interferes with its metabolic processes and thus inhibits their growth. In contrast,
microbial pathogens, viz., bacteria and fungi, have evolved with the complex system to uptake iron from host, including hemoproteins, other iron-binding proteins
(transferrin), and iron chelators called “siderophores” (Cornelis and Matthijs
2002). These are low molecular weight (< 1 kDa) compounds which have strong
affinity for iron; their complexes with iron serve as a means of transport of iron
across the cell membranes. These diverse compounds have great structural and
functional properties (Renshaw et al. 2002).
These “iron carriers” are produced and secreted by bacteria, fungi, and monocotyledons plants under the condition of low iron stress and, thus, serve as carrier for uptaking iron for pathogenic microbes from the host environment.
Figure 2.1 depicts the pathway of uptake of iron (III) by hydroxamate-based
fungal siderophores of Aspergillus fumigates (Moore 2013). The fungal cell wall
is made of chitin and glucan and allows limited permeability of nutrients to periplasmic space and plasma membrane (Farkas 1985). However, this permeability
keeps on altering during different phases of growth. During iron-deficient conditions, the siderophores are released into the external environment and form complex with iron (III) form. This complex is well recognized by membrane proteins
which facilitate the transport of bulky iron-siderophore complex across the cell
S. Bhatia and S. Singh