212
with small molecules such as secondary metabolites but also with antisense oligonucleotides. Note that in recent years, various types of RNAs are becoming wide
used targets for antibacterial drug development. In addition, the search for naturally
occurring short peptides with antibacterial properties is also a promising avenue for
unconventional antibacterial drug discovery (Penchovsky and Traykovska 2015).
Next in this chapter, we discuss all these unconventional approaches of antibacterial
drug discovery in detail.
9.6 Antibacterial Drug Discovery Based
on Antisense Oligonucleotides
Antisense oligonucleotides are short, synthetic, single stranded oligonucleotides
that mimic the structure of RNA, and are capable of inhibiting RNA translation
through two specific mechanisms and reducing the expression of a specific
protein(s). The application of antisense oligonucleotides results in the prevention of
the translation of targeted genes at the mRNA level (Penchovsky and Traykovska
2015). There are three different generations of antisense oligonucleotides, which
possess various chemical modifications and can act in two different ways. The first
generation of antisense oligonucleotides are phosphorothioate-oligo- deoxynucleotides. They can inhibit the target RNAs via the enzymatic function of RNase H
under multiple turnover conditions. The second generation antisense oligonucleotides have a methyl modification at the 2′-OH group of the ribose (-O-CH3). The
third generation of the antisense oligonucleotides includes peptic nucleic acid
(PNA), locked nucleic acid (LNA) and phosphorodiamidate morpholino oligomers
(PMOs). They act by blocking mRNA translation like the second generation antisense oligonucleotides. Note that chimeric antisense oligonucleotides can be
designed to combine the first generation (in the middle) and the second generation
(at both ends) modifications, which will be functioning via RNase cleavage
(Penchovsky and Traykovska 2015).
In the last decade, several antisense oligonucleotides are under clinical development (Rinaldi and Wood 2018; Geary 2009; Meng et al. 2015; Singh et al. 2007;
Wright 2009; Sully and Geller 2016; Stein and Castanotto 2017) that demonstrates
the general applicability of various types of antisense oligonucleotides as drug candidates. There are a great number of essential genes in bacteria with different
sequence to humans that can be used as potential targets of antisense oligonucleotides for antibacterial drug development. A specific advantage that bacterial
genomes possess in comparison to human genomes is that bacterial genomes are
smaller and relatively simply organized. Therefore, it is easy to consider proper
bacterial RNAs as a potential target for antisense oligonucleotides. Such RNA targets should be present in bacteria only and not in humans. For instance, the targeted
RNA can encode an enzyme for the synthesis of an essential metabolite. To assure
that bacteria are not going to survive even if an essential metabolite is present in the
A. Valsamatzi-Panagiotou et al.
with small molecules such as secondary metabolites but also with antisense oligonucleotides. Note that in recent years, various types of RNAs are becoming wide
used targets for antibacterial drug development. In addition, the search for naturally
occurring short peptides with antibacterial properties is also a promising avenue for
unconventional antibacterial drug discovery (Penchovsky and Traykovska 2015).
Next in this chapter, we discuss all these unconventional approaches of antibacterial
drug discovery in detail.
9.6 Antibacterial Drug Discovery Based
on Antisense Oligonucleotides
Antisense oligonucleotides are short, synthetic, single stranded oligonucleotides
that mimic the structure of RNA, and are capable of inhibiting RNA translation
through two specific mechanisms and reducing the expression of a specific
protein(s). The application of antisense oligonucleotides results in the prevention of
the translation of targeted genes at the mRNA level (Penchovsky and Traykovska
2015). There are three different generations of antisense oligonucleotides, which
possess various chemical modifications and can act in two different ways. The first
generation of antisense oligonucleotides are phosphorothioate-oligo- deoxynucleotides. They can inhibit the target RNAs via the enzymatic function of RNase H
under multiple turnover conditions. The second generation antisense oligonucleotides have a methyl modification at the 2′-OH group of the ribose (-O-CH3). The
third generation of the antisense oligonucleotides includes peptic nucleic acid
(PNA), locked nucleic acid (LNA) and phosphorodiamidate morpholino oligomers
(PMOs). They act by blocking mRNA translation like the second generation antisense oligonucleotides. Note that chimeric antisense oligonucleotides can be
designed to combine the first generation (in the middle) and the second generation
(at both ends) modifications, which will be functioning via RNase cleavage
(Penchovsky and Traykovska 2015).
In the last decade, several antisense oligonucleotides are under clinical development (Rinaldi and Wood 2018; Geary 2009; Meng et al. 2015; Singh et al. 2007;
Wright 2009; Sully and Geller 2016; Stein and Castanotto 2017) that demonstrates
the general applicability of various types of antisense oligonucleotides as drug candidates. There are a great number of essential genes in bacteria with different
sequence to humans that can be used as potential targets of antisense oligonucleotides for antibacterial drug development. A specific advantage that bacterial
genomes possess in comparison to human genomes is that bacterial genomes are
smaller and relatively simply organized. Therefore, it is easy to consider proper
bacterial RNAs as a potential target for antisense oligonucleotides. Such RNA targets should be present in bacteria only and not in humans. For instance, the targeted
RNA can encode an enzyme for the synthesis of an essential metabolite. To assure
that bacteria are not going to survive even if an essential metabolite is present in the
A. Valsamatzi-Panagiotou et al.