4
1 Antibacterials
measures and vaccines, as well as biological and chemical therapies based on
viruses or small molecule antibacterials or antibiotics. Strictly speaking antibiotics
are substances produced by microorganisms that compromise the survival of other
microorganisms generally, while an antibacterial negatively impacts, either directly
or indirectly, on the growth or survival of bacteria. Antibacterials can thus be either
naturally derived or accessible through total laboratory synthesis, or semi-synthesis
involving modification of a natural product precursor. The broader term ‘antibacterial’ is thus used for the most part in this book rather than the term ‘antibiotic’
although, arguably, the division between natural vs synthetic (or semi-synthetic) is a
somewhat tenuous one. Humans are intrinsically part of nature not apart from it, and
in that sense ‘synthetic’ is also ‘natural’ since the synthesis of new antibacterials in
laboratories involves humans or human-made or designed automated processes.
Not consciously making the natural-synthetic division can help to inform antibacterial design in interesting new ways. For example, the recognition of the human
microbiome itself as a producer of antimicrobial agents, mainly peptidic antimicrobials, is opening up new possibilities for design and synthesis and potentially
in vivo manipulation of such agents. One wonders also about non-peptidic small
molecules being produced as direct antibacterials or as a part of combinations which
might include activity against resistance mechanisms within the human microbiome
complex and/or in human tissues as part of a supplementary defense protocol against
bacterial pathogens (Garcia-Gutierrez et al. 2019).
Streptomyces, a bacterial genus known for producing antibiotics, has been identified in the human gut microbiome (Seipke et al. 2012; Bolourian and Mojtahedi 2018)
and in association with human lung tissue for example, where a particular Streptomyces sp. TR1341 was isolated and the secondary metabolites produced were implicated in a range of bioactivities including antibacterial activity against some Grampositive and Gram-negative bacterial pathogens (Herbrík et al. 2020). Additionally
genomes for cyanobacteria have also been detected in the human gut microbiota
(Almeida et al. 2019), one such being from a non-photosynthetic cyanobacterialrelated clade known as Melainabacteria. Photosynthetic cyanobacteria are known
to produce a range of biologically active peptidic and non-peptidic metabolites
including some with antibacterial activity (Dixit and Suseela 2013), for example
the hapalindoles from two cultured cyanobacteria (Kim et al. 2012). The structure of
hapalindole A is shown in Fig. 1.1a and the related indole-fused isonitrile compound
ambiguine I isonitrile (Raveh and Carmeli 2007), from another species of cyanobacteria, in Fig. 1.1b. Both hapalindole A and ambiguine I isonitrile show good antibacterial activity and hapalindole A is very potent against Mycobacterium tuberculosum.
Perhaps the non-photosynthetic relatives could also produce antibacterial metabolites and possibly with multi-targeting actions. By thinking outside the ‘natural’ or
‘biological’ square as such and by considering a more global natural-synthetic square,
new design possibilities are likely to emerge, including advances from looking more
at how best to work with nature and enhance it.
1 Antibacterials
measures and vaccines, as well as biological and chemical therapies based on
viruses or small molecule antibacterials or antibiotics. Strictly speaking antibiotics
are substances produced by microorganisms that compromise the survival of other
microorganisms generally, while an antibacterial negatively impacts, either directly
or indirectly, on the growth or survival of bacteria. Antibacterials can thus be either
naturally derived or accessible through total laboratory synthesis, or semi-synthesis
involving modification of a natural product precursor. The broader term ‘antibacterial’ is thus used for the most part in this book rather than the term ‘antibiotic’
although, arguably, the division between natural vs synthetic (or semi-synthetic) is a
somewhat tenuous one. Humans are intrinsically part of nature not apart from it, and
in that sense ‘synthetic’ is also ‘natural’ since the synthesis of new antibacterials in
laboratories involves humans or human-made or designed automated processes.
Not consciously making the natural-synthetic division can help to inform antibacterial design in interesting new ways. For example, the recognition of the human
microbiome itself as a producer of antimicrobial agents, mainly peptidic antimicrobials, is opening up new possibilities for design and synthesis and potentially
in vivo manipulation of such agents. One wonders also about non-peptidic small
molecules being produced as direct antibacterials or as a part of combinations which
might include activity against resistance mechanisms within the human microbiome
complex and/or in human tissues as part of a supplementary defense protocol against
bacterial pathogens (Garcia-Gutierrez et al. 2019).
Streptomyces, a bacterial genus known for producing antibiotics, has been identified in the human gut microbiome (Seipke et al. 2012; Bolourian and Mojtahedi 2018)
and in association with human lung tissue for example, where a particular Streptomyces sp. TR1341 was isolated and the secondary metabolites produced were implicated in a range of bioactivities including antibacterial activity against some Grampositive and Gram-negative bacterial pathogens (Herbrík et al. 2020). Additionally
genomes for cyanobacteria have also been detected in the human gut microbiota
(Almeida et al. 2019), one such being from a non-photosynthetic cyanobacterialrelated clade known as Melainabacteria. Photosynthetic cyanobacteria are known
to produce a range of biologically active peptidic and non-peptidic metabolites
including some with antibacterial activity (Dixit and Suseela 2013), for example
the hapalindoles from two cultured cyanobacteria (Kim et al. 2012). The structure of
hapalindole A is shown in Fig. 1.1a and the related indole-fused isonitrile compound
ambiguine I isonitrile (Raveh and Carmeli 2007), from another species of cyanobacteria, in Fig. 1.1b. Both hapalindole A and ambiguine I isonitrile show good antibacterial activity and hapalindole A is very potent against Mycobacterium tuberculosum.
Perhaps the non-photosynthetic relatives could also produce antibacterial metabolites and possibly with multi-targeting actions. By thinking outside the ‘natural’ or
‘biological’ square as such and by considering a more global natural-synthetic square,
new design possibilities are likely to emerge, including advances from looking more
at how best to work with nature and enhance it.