9 Antimicrobial Compounds
Discovery of antibiotics was a success story of mankind in many respects, enabling
various basic medical studies, sophisticated surgical operations, and cancer therapies. Peak of the discovery of new antibiotics was soon after developing large-scale
production of penicillin. Several classes of antibiotics were found in the 1950s and
1960s. After that “golden age,” the main work was focused on chemical derivatization of known antibiotics. After the 1960s, the number of new useful antibiotics has
diminished even when the needs have increased. The overuse of antibiotics for
human and animal health has caused generation of multiresistant microbes. The
rise in drug resistance for curing of microbial infections is not only life-threatening
but also has a wider socioeconomic impact on mankind (http://www.un.org/
sustainabledevelopment/sustainable-development-goals). Due to international
efforts, the number of new drugs in pipelines has slightly increased during the last
few years, but these efforts are far from adequate (WHO/EMP/IAU/2017.11). The
cited WHO report lists the state of art in the main antibiotic classes as well as the
priority for the pathogens. A new antibiotic is considered to be novel, if it (1) has no
cross-resistance to existing antibiotics, (2) belongs to a new chemical class, (3) has a
new physiological target, and (4) has new mechanism of action. Although many
antibiotics have been proven to be efficient against Gram-positive bacteria, the
situation with the Gram-negative pathogens is worse because of their complex
membrane system. The WHO report focused on bacterial pathogens, but related
problems exist as to other microbial pathogen groups and parasites.
How could alkaliphilic microbes serve as sources of novel antibiotics? Like other
microbes, alkaliphiles certainly produce bioactive agents for competitive advantage.
However, the research on the alkaliphiles was not conducted at the time of the
“golden age” of antibiotics. Moreover, the pH o (extracellular) is much higher than
pH i (intracellular); thus, the antibiotics must be alkali resistant and be able to bind or
enter the cell. The entrance of the small-molecule antibiotics to bacterial cells might
also be provided by cell wall-hydrolyzing enzymes which may weaken the cell wall
(a role of some secreted enzymes of alkaliphiles?). One aspect is that the producer of
an antibiotic must be itself “immune” to it. This might sometimes offer a key to study
the mechanism of action of the produced antibiotics.
The maintenance of internal pH of alkaliphiles shall operate safely to avoid large
pH fluctuations inside the cell. The maintenance system is based on cell wall and cell
membrane and system containing ionic channels. Presumably, these channels are
especially important for the surveillance of alkaliphiles. The diffusion rate of protons
is extremely high, and their leakage to outside of the cell can be fatal. In all cells, the
entrance of nutrients and ions through pores and channels is a weak point. There are
many known antibiotics acting as ionophores and disturbing this traffic (e.g.,
bacteriocins, gramicidin, and valinomycin). It is conceivable that alkaliphiles have
developed different strategies for protecting and attacking (microbe-microbe competition) the pores and channels in the cell membrane. Therefore, novel antibiotics
180
E. Khalikova et al.
Discovery of antibiotics was a success story of mankind in many respects, enabling
various basic medical studies, sophisticated surgical operations, and cancer therapies. Peak of the discovery of new antibiotics was soon after developing large-scale
production of penicillin. Several classes of antibiotics were found in the 1950s and
1960s. After that “golden age,” the main work was focused on chemical derivatization of known antibiotics. After the 1960s, the number of new useful antibiotics has
diminished even when the needs have increased. The overuse of antibiotics for
human and animal health has caused generation of multiresistant microbes. The
rise in drug resistance for curing of microbial infections is not only life-threatening
but also has a wider socioeconomic impact on mankind (http://www.un.org/
sustainabledevelopment/sustainable-development-goals). Due to international
efforts, the number of new drugs in pipelines has slightly increased during the last
few years, but these efforts are far from adequate (WHO/EMP/IAU/2017.11). The
cited WHO report lists the state of art in the main antibiotic classes as well as the
priority for the pathogens. A new antibiotic is considered to be novel, if it (1) has no
cross-resistance to existing antibiotics, (2) belongs to a new chemical class, (3) has a
new physiological target, and (4) has new mechanism of action. Although many
antibiotics have been proven to be efficient against Gram-positive bacteria, the
situation with the Gram-negative pathogens is worse because of their complex
membrane system. The WHO report focused on bacterial pathogens, but related
problems exist as to other microbial pathogen groups and parasites.
How could alkaliphilic microbes serve as sources of novel antibiotics? Like other
microbes, alkaliphiles certainly produce bioactive agents for competitive advantage.
However, the research on the alkaliphiles was not conducted at the time of the
“golden age” of antibiotics. Moreover, the pH o (extracellular) is much higher than
pH i (intracellular); thus, the antibiotics must be alkali resistant and be able to bind or
enter the cell. The entrance of the small-molecule antibiotics to bacterial cells might
also be provided by cell wall-hydrolyzing enzymes which may weaken the cell wall
(a role of some secreted enzymes of alkaliphiles?). One aspect is that the producer of
an antibiotic must be itself “immune” to it. This might sometimes offer a key to study
the mechanism of action of the produced antibiotics.
The maintenance of internal pH of alkaliphiles shall operate safely to avoid large
pH fluctuations inside the cell. The maintenance system is based on cell wall and cell
membrane and system containing ionic channels. Presumably, these channels are
especially important for the surveillance of alkaliphiles. The diffusion rate of protons
is extremely high, and their leakage to outside of the cell can be fatal. In all cells, the
entrance of nutrients and ions through pores and channels is a weak point. There are
many known antibiotics acting as ionophores and disturbing this traffic (e.g.,
bacteriocins, gramicidin, and valinomycin). It is conceivable that alkaliphiles have
developed different strategies for protecting and attacking (microbe-microbe competition) the pores and channels in the cell membrane. Therefore, novel antibiotics
180
E. Khalikova et al.