222
positive and Gram negative bacteria but even so, it has weak antibacterial activity.
However, different modifications of its structure demonstrate the potential of this
cell penetrating peptide. For example, Pep-1-K has replaced 3 glutamate residues
(Glu-2, Glu-6, and Glu-11) with lysine (Zhu et al. 2006). As a result, the antibacterial activity is significantly increased towards Gram positive and Gram negative
bacteria, in addition to clinical isolates of multi drug resistant Pseudomonas aeruginosa and methicillin resistant Staphylococcus aureus (Kauffman et al. 2015). Tat is
the minimal transduction domain derived from human immunodeficiency virus-1
(HIV-1) Tat protein (Lv et al. 2017). It consists of 9 amino acid residues and it is an
arginine rich peptide. It shows no toxicity in human erythrocytes. According to
Splith et al., tat demonstrates the inhibitory effect in various Gram positive and
Gram negative bacteria such as S. aureus (Splith and Neundorf 2011).
Indeed, the general inability of resistance development against antimicrobial
peptides and cell penetrating peptides gives them a great advantage in comparison
to antibiotics. Pharmaceutical companies have invested in antimicrobial peptides
and cell penetrating peptides research as a potential future therapeutic option.
Furthermore, a lot of antimicrobial peptides already reached the markets and there
are many in preclinical along with clinical trials that are on process nowadays
(Boparai and Sharma 2019).
9.10 Conclusion
Eventually, bacteria may develop resistance against any antibiotic. In recent years,
the rate of emergence of antimicrobial resistance is constantly increasing due to the
widespread misuse of antibiotics both in human and veterinary medicine. As a
result, more people are dying worldwide by infections caused by drug resistant
bacterial pathogens. We need to tackle this problem by applying two main strategies. The first one is to significantly reduce the misuse of antibiotics worldwide. The
second general approach we need to employ is to develop novel much more efficient
approaches to antimicrobial drug development. For instance, we can apply antisense
oligonucleotide technology for inhibition of any bacterial RNA that is a suitable
drug target. We can use various types of cell penetrating oligopeptides attached to
the antisense oligonucleotides for their delivering into the bacterial cell. Applying
such drug design approaches can significantly reduce the time and the cost of antimicrobial drug development because of the main principles of design and application of antisense oligonucleotides are well understood. Even when bacteria develop
resistance against an antisense oligonucleotide by mutating the target sequence, we
can easily address that by manipulating the design of antisense oligonucleotide.
Acknowledgments This work was financed by a grant DN/13/14/20.12.2017 awarded by the
Bulgarian National Science Fund (BNSF).
A. Valsamatzi-Panagiotou et al.
positive and Gram negative bacteria but even so, it has weak antibacterial activity.
However, different modifications of its structure demonstrate the potential of this
cell penetrating peptide. For example, Pep-1-K has replaced 3 glutamate residues
(Glu-2, Glu-6, and Glu-11) with lysine (Zhu et al. 2006). As a result, the antibacterial activity is significantly increased towards Gram positive and Gram negative
bacteria, in addition to clinical isolates of multi drug resistant Pseudomonas aeruginosa and methicillin resistant Staphylococcus aureus (Kauffman et al. 2015). Tat is
the minimal transduction domain derived from human immunodeficiency virus-1
(HIV-1) Tat protein (Lv et al. 2017). It consists of 9 amino acid residues and it is an
arginine rich peptide. It shows no toxicity in human erythrocytes. According to
Splith et al., tat demonstrates the inhibitory effect in various Gram positive and
Gram negative bacteria such as S. aureus (Splith and Neundorf 2011).
Indeed, the general inability of resistance development against antimicrobial
peptides and cell penetrating peptides gives them a great advantage in comparison
to antibiotics. Pharmaceutical companies have invested in antimicrobial peptides
and cell penetrating peptides research as a potential future therapeutic option.
Furthermore, a lot of antimicrobial peptides already reached the markets and there
are many in preclinical along with clinical trials that are on process nowadays
(Boparai and Sharma 2019).
9.10 Conclusion
Eventually, bacteria may develop resistance against any antibiotic. In recent years,
the rate of emergence of antimicrobial resistance is constantly increasing due to the
widespread misuse of antibiotics both in human and veterinary medicine. As a
result, more people are dying worldwide by infections caused by drug resistant
bacterial pathogens. We need to tackle this problem by applying two main strategies. The first one is to significantly reduce the misuse of antibiotics worldwide. The
second general approach we need to employ is to develop novel much more efficient
approaches to antimicrobial drug development. For instance, we can apply antisense
oligonucleotide technology for inhibition of any bacterial RNA that is a suitable
drug target. We can use various types of cell penetrating oligopeptides attached to
the antisense oligonucleotides for their delivering into the bacterial cell. Applying
such drug design approaches can significantly reduce the time and the cost of antimicrobial drug development because of the main principles of design and application of antisense oligonucleotides are well understood. Even when bacteria develop
resistance against an antisense oligonucleotide by mutating the target sequence, we
can easily address that by manipulating the design of antisense oligonucleotide.
Acknowledgments This work was financed by a grant DN/13/14/20.12.2017 awarded by the
Bulgarian National Science Fund (BNSF).
A. Valsamatzi-Panagiotou et al.