Progress in Microbes and Molecular Biology
Review Article
1
The Rising of “Modern Actinobacteria” Era
Jodi Woan-Fei Law1, Vengadesh Letchumanan1, Loh Teng-Hern Tan1, Hooi-Leng Ser1, Bey-Hing
Goh2, Learn-Han Lee1*
1Novel Bacteria and Drug Discovery Research Group (NBDD), Microbiome and Bioresource Research Strength (MBRS),
Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, 47500 Bandar Sunway, Selangor
Darul Ehsan, Malaysia.
2Biofunctional Molecule Exploratory Research Group (BMEX), School of Pharmacy, Monash University Malaysia, 47500
Bandar Sunway, Selangor Darul Ehsan, Malaysia.
Abstract: The term “Modern Actinobacteria” (MOD-ACTINO) was coined by a Malaysian Scientist Dr. Lee Learn-Han,
who has great expertise and experience in the field of actinobacteria research. MOD-ACTINO is defined as a group of
actinobacteria capable of producing compounds that can be explored for modern applications such as development of
new drugs and cosmeceutics. MOD-ACTINO members consist of already identified or novel actinobacteria isolated from
special environments: mangrove, desert, lake, hot spring, cave, mountain, Arctic and Antarctic regions. These actinobac-
teria are valuable sources for various industries which can contribute directly/indirectly towards the improvement in many
aspects of our lives.
Keywords: modern; bioactive; actinobacteria;
environment; bioprospecting
Received: 16th February 2020
Accepted: 23rd March 2020
Published Online: 29th March 2020
Citation: Law JW-F, Letchumanan V, Tan LT-H et al. The Rising of “Modern Actinobacteria” Era. Prog Microbe Mol Biol
2020; 3(1): a0000064. https://doi.org/10.3687/pmmb.a0000064
INTRODUCTION
The Actinobacteria has a long evolutionary history for it
has existed on earth around 2.7 billion years ago, ante-
ceding the Great Oxidation event that occurred 2.3 bil-
lion years ago[1, 2]. In the Bacteria kingdom, ancient Acti-
nobacteria is one of the major phyla associated with the
early colonization of land and they play important roles
in assisting Earth’s ecosystems function[2]. As one of the
most primitive lineages among prokaryotes, actinobacte-
ria have extraordinary diversity of morphology and func-
tion[3,4]. This phylum consists of free-living Gram-positive
bacteria with a variety of morphological features includ-
ing coccus, rod, and complex fragmenting hyphal that
develops into branched mycelium[3,5]. These bacteria can
be found predominantly in terrestrial soil and marine eco-
systems[6]. Actinobacteria have significant functions, for
instances, they are important agents of global carbon and
nitrogen cycles; agents of bioremediation; probiotics in
humans and animals; pathogens of humans, animals and
plants; producers of enzymes and clinically important me-
tabolites[1,3,7].
Following the pioneering research led by Professor
Waksman, the ’52 Nobel laureate who revealed strep-
tomycin antibiotic from Streptomyces griseus, actino-
bacteria have since become the “star” in the scientific
community[8,9]. Essentially, the investigation of novel
Actinobacteria (genera or species) and bioprospecting
of active isolates have intensified around the world,
often through random large-scale sampling of environ-
ment, selective isolation and subsequently bioactivity
screening of isolates[6]. This resulted in the discovery
and screening of over thousands of species of actinobac-
teria. Historically, the actinobacteria were documented
as a controversial kind of microorganisms due to their
diverse and unique appearances, for which, several of
them resemble the appearance of fungi[10]. The taxono-
my of phylum Actinobacteria has been revised over time
and the recent roadmap has been proposed with 6 major
classes in the phylum, namely: Actinobacteria, Acidimi-
crobiia, Coriobacteriia, Nitriliruptoria, Rubrobacteria,
and Thermoleophilia. Class Actinobacteria is the largest
among others as it consists of 15 orders: Actinomyceta-
les, Actinopolysporales, Bifidobacteriales, Catenulispo-
Copyright 2020 by Law JW-F and HH Publisher. This work under licensed under the Creative Commons Attribution-NonCommercial
4.0 International Lisence (CC-BY-NC4.0)
*Correspondence: Learn-Han Lee, Novel Bacteria and
Drug Discovery Research Group (NBDD), Microbiome
and Biore-source Research Strength (MBRS), Jeffrey
Cheah School of Medicine and Health Sciences, Monash Uni-
versity Malaysia, 47500 Bandar Sunway, Selangor Darul
Ehsan, Malaysia. lee. learn.han@monash.edu
2
rales, Corynebacteriales, Glycomycetales, Jiangellales,
Kineosporiales, Micrococcales, Micromonosporales,
Propionibacteriales, Pseudonocardiales, Streptomyceta-
les, Streptosporangiales, and Frankiales[11,12]. The genus
Streptomyces (order: Streptomycetales, family: Strepto-
mycetaceae) is the most famous actinobacteria as they
have been greatly studied due to their tremendous bioac-
tive potentials[7].
THE ERA OF MODERN Actinobacteria (MOD-
ACTINO)
Actinobacteria have been distinguished for their prolific
production of antibiotics. From the 1950s to 1970s, ap-
proximately 60% of new antibiotics were predominantly
isolated from streptomycetes[13]. Eventually, researchers
have further exposed the presence of actinobacteria in
special and extreme environments with the increasing
efforts to discover new metabolites from various mi-
crobial sources. This essentially leads to a significant
paradigm shift in the exploration of Actinobacteria, such
instances include the isolation of actinobacteria from
underexplored unique habitats and the investigation of
their secondary metabolites with different activities other
than antimicrobials (e.g. antioxidant, anticancer)[14]. Fur-
thermore, the non-Streptomyces genera (e.g. Sinomonas,
Microbacterium, Nocardia) which referred as the “rare
Actinobacteria” have shown growing importance as valu-
able sources in discovery of novel bioactive secondary
metabolites[15]. Malaysia Research Star Award winner, Dr.
Lee Learn Han — who has great expertise and experience
in the field of actinobacteria research, coined the term
“Modern Actinobacteria” (MOD-ACTINO) to define ac-
tinobacteria with modern applications (Figure 1). In this
context, the term refers to actinobacteria that synthesize
natural products with new interesting bioactivities in re-
cent years, for examples, drug leads with anti-viral (HIV),
anti-protozoa (malaria), antioxidant, and neuroprotection
properties as well as compounds utilized for cosmetic
formulation. In addition, this term covers actinobacteria
which produce approved drugs and have been subjected
to drug repurposing effort. MOD-ACTINO also inclusive
of known or novel actinobacteria that have been discov-
ered from special environments.
The Rising of...
Figure 1. The ideas of “Modern Actinobacteria” (MOD-ACTINO) proposed by Dr. Lee Learn Han.
By the end of 20th century, actinobacterial natural prod-
ucts have been found to exert extensive biological activi-
ties comprising antibacterial (against antibiotic resistant
strains), antifungal, antiparasitic, immunosuppressant,
antioxidant, and anticancer agents[8,16–22], Numerous acti-
nobacterial bioactive compounds are well-known for the
treatment of plant, animal, and human diseases. For in-
stances, kasugamycin is a marketed antifungal antibiotic
produced from Streptomyces kasugaensis which used for
the control of rice blast caused by phytopathogenic fun-
gus Magnaporthe oryzae[23,24]. Moreover, several chemo-
therapeutic drugs such as bleomycin (from Streptomyces
verticillus) and doxorubicin (from Streptomyces peuce-
tius) that have been introduced into clinical use are of
actinobacterial origin[25–27]. Another remarkable drug dis-
covery event from genus Streptomyces is achieved by Pro-
fessor William C. Campbell and Professor Satoshi Omura
through the isolation of a new “miracle” drug avermectin
from Streptomyces avermitilis (renamed as Streptomyces
avermectinius)[28]. Avermectin was later being refined into
the safest and most potent derivative known as ivermec-
tin. Ivermectin is an antiparasitic drug effective against
helminths, arachnids and insects. It was marketed in 1981
for veterinary use around the world and subsequently ap-
proved for human use in 1987. Ivermectin is administered
for treatment of onchocerciasis and lymphatic filariasis in
many parts of the world. This “miracle” drug has revolu-
tionized the treatment of these devastating parasitic dis-
3
Law JW-F et al.
eases, thereby improving the health of millions of individ-
uals. Resultantly, the 2015 Nobel Prize in Physiology or
Medicine was awarded (with one half jointly) to Professor
William C. Campbell and Professor Satoshi Omura[28,29].
Research on actinobacteria is still ongoing as they never
cease to amaze us with their vast potential of bioactive
secondary metabolite production. Studies conducted
nowadays, towards the 21st century, have gradually re-
vealed the immense ability of actinobacteria in produc-
ing compounds with new captivating bioactivities far
more than expected. This is witnessed through findings
of compounds with in vitro anti-human immunodeficien-
cy virus (HIV) activity produced by actinobacteria[30–32].
One of the earliest research studies on this was reported
by Chokekijchai et al. (1995)[33], for which a new anti-
HIV polypeptide was obtained from a Streptomyces sp.
isolated from soil sample collected in Japan. Besides, a
recent study conducted by Ding et al. (2010)[34] had suc-
cessfully isolated a novel pentacyclic indolosesquiterpene
— xiamycin produced by mangrove-derived Streptomy-
ces sp. GT2002/1503 which is active against HIV. Apart
from anti-HIV activity, a number of actinobacteria were
documented to produce compounds (e.g. borrelidin, meta-
cycloprodigiosin, bafilomycin A1) with promising activity
against human malaria parasite (Plasmodium falciparum)
[35–37]. Furthermore, studies also reported the production of
neuroprotective substances by actinobacteria that may be
potential medicines for brain ischemia and other neurode-
generative diseases such as multiple sclerosis, Parkinson’s
diseases, and Alzheimer’s disease[38,39]. As an example,
Hayakawa et al. (2013)[40] revealed a new neuroprotective
compound isolated from Streptomyces sp. RAI20 - indan-
ostatin, which is also the first reported 1,3-indanone from
bacteria. The compound was found to partially protect C6
glioma cells (derived from rat neural tumors induced by
N-nitrosomethylurea) against glutamate toxicity which
could be useful as treatment for cerebral ischemic disor-
ders.
Likewise, the possibility of incorporating actinobacte-
rial bioactive metabolites in modern skin care cosmetics
has further uplift the value of MOD-ACTINO. The hu-
man skin is the largest organ of our integumentary sys-
tem which could face esthetic issues such as freckles,
acne, and aging. Dahal et al. (2016)[41] proposed the ad-
dition of actinobacterial derived resources into cosmetics
products for beneficial effects which could enhance the
appearance of human skin such as anti-acne, anti-aging,
skin whitening, and antioxidant effects. In the study, 12
strains of actinobacteria belonging to the genera Strepto-
myces, Actinokineospora, and Calidifontibacter exhibited
antibacterial activity against skin pathogens Staphylococ-
cus epidermidis and Propionibacterium acnes. The crude
supernatant of these actinobacteria also demonstrated
promising tyrosinase inhibition, elastase inhibition, and
antioxidant activities. Another research conducted by Tan
et al. (2019)[42] had reported the isolation of a mangrove
Streptomyces sp. MUM273b which possessed antioxidant
and UVB protective properties. Hence, actinobacterial
derived resources can be added to cosmetics applications
to improve skin conditions by providing skin whitening
effects, acne vulgaris treatment, anti-aging effects, anti-
oxidant effects, and anti-UV properties.
Interestingly, there is an increasing number of studies that
support the concept of using actinobacteria as probiotics
in animal feed especially for aquaculture[43]. Probiotics in
aquaculture are expected to confer health benefits to the
host such as growth enhancement, improvement in nutrient
digestion and immune response, also, to assist in preven-
tion of bacterial infection through production of inhibitory
compounds[43,44]. A few number of studies have suggested
the utilization of actinobacteria as potential probiotic strains
against shrimp and fish pathogenic Vibrio spp.[45–49]. Mean-
while, the members of Streptomyces and Bacillus are also
compelling probiotic strains as they have been shown to
be capable of promoting growth and increasing resistance
against bacterial infections in fishes and shrimps[50–52]. Most
studies recommended the genus Streptomyces as the most
potent actinobacteria probiotic for aquaculture mainly due to
their ability to produce a multitude of extracellular enzymes
and antibiotics, and to form heat- and desiccation-resistant
spores[44,50]. Therefore, these MOD-ACTINO will be a great
asset to the biopharmaceutical, agriculture, aquaculture, and
cosmetic industries.
Aside from the exploration of actinobacteria-derived com-
pounds for development of novel drugs, research also em-
phasizes on the investigation of drug repurposing. Drug
repurposing (drug repositioning/reprofiling/retasking) is
defined as an approach to search for new applications of ap-
proved or investigational drugs that are beyond the scope
of the original medical indication[53]. Previously approved
actinobacteria-derived drugs such as rapamycin (sirolimus;
produced by Streptomyces hygroscopicus) was initially
known as an antifungal agent[54]. Rapamycin was approved
as an immunosuppressant for the prevention of allograft re-
jection in 1999 due to its strong suppression of interleukin-2
(IL-2)-stimulated T cell proloferation[55]. It is a macrolide
and an allosteric inhibitor of mammalian target of rapamy-
cin (mTOR)[55,56]. The mTOR is a serine/threonine protein
kinase and it is often upregulated in different types of can-
cers. As a result, researchers are determined to examine its
anticancer potentials. Rapamycin has been verified to be a
potent immunosuppressant and a promising anticancer/an-
titumor agent that can be used as a single agent or in drug
combination[57–59]. Thus, this demonstrated one of the crite-
ria of MOD-ACTINO where the actinobacterial compounds
exhibited different bioactivities from their originally identi-
fied bioactivity.
PRESENCE OF MOD-ACTINO IN SPECIAL ENVI-
RONMENTS
Actinobacteria are sporulating organisms that possessed
astonishing capability to generate extraordinary proper-
ties[60–62]. This is often associated with their complex mor-
phological changes in their multicellular life cycle and their
large genome size as observed particularly in streptomyce-
tes[3,11,63]. The complexity of these organisms has enabled
them to thrive in extreme and special environments[15] such
as the Arctic and Antarctic regions[64,65], mountain planta-
tions[66], glaciers[67], caves[68], deserts[69], hot springs[70], and
mangroves[71–75]. These environments are special in terms of
physical parameters (e.g. unusually high/low temperature,
4
radiation, pressure) or chemical conditions (e.g. acidic/
alkaline pH, high salinity, low levels of nutrients and
moisture)[76,77]. The actinobacteria evolved by developing
unique defense mechanism that enables them to survive
under hostile and extreme conditions. Consequently, acti-
nobacteria from special and extreme environments may be
thermotolerant, acidtolerant, alkalitolerant, psychrotoler-
ant, halotolerant, haloalkalitolerant or xerophilous[76].
In addition, several novel genera/species have been discov-
ered from these special environments. For instances, Mumia
flava gen. nov., sp. nov. (family Nocardioidaceae)[78], Bar-
rientosiimonas humi gen. nov., sp. nov. (family Dermacoc-
caceae)[79], and Monashia flava gen. nov., sp. nov. (family
Intrasporangiaceae)[80] were each novel species of a new
genus isolated from mangroves in Malaysia; Actinocrinis
puniceicyclus gen. nov., sp. nov. (family Actinospicaceae)
[81] isolated from acidic spring; and Desertiactinospora ge-
latinilytica gen. nov., sp. nov. (family Streptosporangia-
ceae) isolated from desert[82]. Besides, other novel species
of rare actinobacteria were also identified such as Micro-
bacterium mangrovi sp. nov.[83] and Sinomonas humi sp.
nov.[84] from mangroves; Rhodococcus kroppenstedtii sp.
nov.[85] and Micromonospora acroterricola sp. nov.[86] from
desert; and Nonomuraea monospora sp. nov.[87] from cave
soil. In fact, recent studies also uncovered many novel bio-
active actinobacteria which originated from these unique
niches. There are multiple novel Streptomyces strains re-
covered from mangrove environments with useful bioac-
tivities, for examples, Streptomyces colonosanans sp. nov.
(antioxidant and anticancer)[88], Streptomyces monashensis
(antioxidant and anticancer)[27,89], Streptomyces mangro-
visoli sp. nov. (antioxidant)[90], Streptomyces pluripotens
sp. nov. (antibacterial)[91], and Streptomyces malaysiense
sp. nov. (antioxidant and anticancer)[92]. Many compounds
produced by MOD-ACTINO exhibit important properties
which can be developed into new drugs/drug leads with
higher efficacy in the near future.
HARNESSING THE POTENTIALS OF MOD-ACTI-
NO AND CONCLUSIONS
With the growing importance of actinobacteria in various
fields, the advancement in molecular biology especially in
this post-genomic era can assist us to reach a higher lev-
el of understanding of these organisms by studying their
genome. The availability of next generation sequencing
(NGS) technologies and the -omics methods (metagenom-
ics, metaproteomics) have greatly assisted in overcoming
the issue on detection of unculturable bacteria as well as
contributed to the research on actinobacteria biosynthetic
gene clusters and their secondary metabolites production[93].
Lately, there is an increase in the number of new genome
sequences of actinobacteria which have been made avail-
able to the public. Majority of them were resulted from
projects aimed to understand the connection of secondary
metabolites productions or to evaluate new actinobacterial
natural products to their biosynthetic pathways via genome
mining[94]. In particular, the bioactive actinobacteria strains
have been subjected to whole genome sequencing to fur-
ther appreciate their biological importance in bioactive me-
tabolites or enzyme production[95–104]. It is anticipated that
the accessibility to large sets of actinobacterial genome
sequences will provide us a more thorough understanding
of actinobacteria phylogeny and facilitate in the iden-
tification of medically useful new natural products[105].
Members of MOD-ACTINO are valuable sources for
various industries which can contribute directly/indi-
rectly towards the improvement in many aspects of our
lives. MOD-ACTINO will be the “key” microorganisms
to further improve human health and wellbeing in the
modern society.
Authors Contributions
The research and manuscript writing were performed by
JW-FL, VL and L-HL. LT-HT, H-LS and B-HG provided
vital guidance of the research and proof of the writing.
The research project was founded by JW-FL and L-HL.
Conflict of Interest
The authors declare that there is no conflict of interest
in this work.
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