Tafakori AMB Expr (2021) 11:92 https://doi.org/10.1186/s13568-021-01251-3 MINI-REVIEW Open Access Slime molds as a valuable source of antimicrobial agents Vida Tafakori* Abstract Given the emerging multidrug-resistant pathogens, the number of efective antimicrobial agents to deal with the threat of bacterial and fungal resistance has fallen dramatically. Therefore, the critical solution to deal with the missing efective antibiotics is to research new sources or new synthetic antibiotics. Natural products have diferent advan- tages to be considered antimicrobial agents. There are diferent natural sources for antimicrobial agents, such as bac- teria, fungi, algae, slime molds, and plants. This article has focused on antibiotics from slime molds, especially Myxo- mycetes. The reason why slime molds have been chosen to be studied is their unique bioactive metabolites, especially over the past couple of decades. Some of those metabolites have been demonstrated to possess antibiotic activities. Hence, this article has focused on the potential of these creatures as an alternative source of antibiotics. Keywords: Multidrug, Resistance, Antibiotics, Natural products, Myxomycetes Introduction the third leading cause of death in the US behind heart In 1940, Edward Abraham and Ernest Chain at Oxford disease and cancer (Ahmad et al. 2021). Tus, infectious University in the United Kingdom afected the Escheri- diseases are still concerned among the most important chia coli extraction on the penicillin and proved the global social challenge of the world. existence of a penicillinase, which was able to inactivate Reports estimate that, by 2050, 10 million people will penicillin, warning about intrinsic antibiotic resistance. die every year with an estimated economic cost of $100 Tis happened soon after the discovery of penicillin trillion due to antimicrobial resistance unless a global in 1928 when the drug was not being used yet (Amenu response is mounted to this problem (Simpkin et al. 2014). Antibiotics, these “wonder drugs,” were used 2017). Accordingly, the critical solution to deal with the to treat injured soldiers and wounded civilians during missing efective antibiotics is to study on new sources or World War II. However, after penicillin came into clini- new synthetic antibiotics. cal use, the additional bacteria developed the ability to In the antimicrobial resistance process, microbial cells resist other antibiotics, unfortunately. Nowadays, the have developed a complex and redundant barrier to pen- appearance of multidrug-resistant bacteria (Table 1) has etration, enzymes to destroy or modify, and pumps to made antimicrobial resistance a major threat to global efux the antibiotic compounds. Hence, between natu- health and development. Te emerging multidrug-resist- ral products and synthetic ones, the former is preferable ant pathogens have dramatically lowered the number of since as the microbial cells evolve and gain the ability to efective antimicrobial agents to deal with the threat of develop resistance against antimicrobial agents, natural bacterial and fungal resistance. Te provisional leading products also evolve in nature. Another reason is that in cause-of-death rankings for 2020 indicate COVID-19 as the drug discovery sector, synthetic antibiotics are most favor human bioactivity, not suitable for microbial biol- ogy (Wright 2014). On the other hand, natural products *Correspondence: [email protected]; [email protected] refect the true chemical diversity (extensive functional Department of Cell and Molecular Biology, Faculty of Science, Kharazmi group chemistry and chirality), which does not exist University, Tehran, Iran © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. 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Tafakori AMB Expr (2021) 11:92 Page 2 of 12 Table 1 Multidrug resistant bacteria observed in the community (Duin and Paterson 2016) Multidrug resistant (MDR) phenotype Epidemiologic setting of community-onset Major antibiotics resistance mechanisms infections Methicillin-resistant S. aureus (MRSA) Household colonization; farm animal exposure mecA, mecC (emerging) Vancomycin-resistant Enterococci (VRE) Typically health care-associated vanA, vanB Carbapenem-resistant Acinetobacter baumannii Extremely rare Carbapenemases (CRAB) Multi-drug resistant Pseudomonas aeruginosa Extremely rare Extended-spectrum beta-lactamases, carbapen- emases, and efux systems Extended-spectrum beta-lactamase (ESBL)- Endemic in Asia; in low-prevalence areas travel Extended-spectrum beta-lactamases, and efux producing Enterobacteriaceae to Asia systems Carbapenem-resistant Enterobacteriaceae (CRE) Rare at present; emerging in India and China Carbapenemases in synthetic products (Phillipson 2007). On the other products the preferable choice for antimicrobial agent hand, for some natural products, the apparent lack of sources. industrial interest may be due to the inherent time-con- suming working process with natural products, difcul- Natural sources of antimicrobial agents ties in access and supply, costs of collection, extraction, Although antibiotics generally refer to antibacterials, and isolation, and standardization limitations of crude since the term has not exactly been defned, it encom- drugs (Phillipson 2007; Harvey 2008). However, despite passes a wide variety of agents, including antibacterial, all these problems, their advantages still make natural antifungal, antiviral, and antiparasitic drugs (Chees- brough 2006). Fig. 1 The life cycle of a plasmodial slime mold includes sexual and asexual reproduction Tafakori AMB Expr (2021) 11:92 Page 3 of 12 Fig. 2 a Plasmodium of the slime mold Physarum sp. b Sporangia of Physarum polycephalum (https:// calph otos. berke ley. edu) Free amoeba Zygote Sexual production Spores Emerging amoebas Mature fruiting Emerging body with spores amoebas Free amoebas Developing Asexual begin to aggregate fruiting body production Slug or moving Amoeba mass amoeba Fig. 3 Life cycle of a cellular slime mold Tere are diferent natural sources of antimicrobial (Primon-Barros and José Macedo 2017; Han et al. 2011), agents, such as flamentous bacteria actinomycetes (more and other natural sources. than 50% of all antibiotics are produced by these micro- Tere are diferent approaches for efective drug dis- organisms), non-flamentous bacteria (10–15%) (Demain covery programs: bioactive-guided screening, chemical 2014; Salehghamari et al. 2015), microscopic fungi screening, target-oriented screening, the use of unex- (about 20% of all antibiotics are produced by flamen- plored strains, genome mining (using next-generation tous fungi) (Demain 2014), slime molds, algae (Ibrahim DNA sequencing), and activation of silent gene clusters and Lim 2015; Pane et al. 2015), plants (Abreu et al. 2012; (Wohlleben et al. 2016). Among diferent natural sources Tafakori and Nasiri 2018; Eftekhar et al. 2005), animals mentioned above, some have received extra attention, Tafakori AMB Expr (2021) 11:92 Page 4 of 12 Fig. 4 a Fuligo septica, b Physarum gyrosum c Arcyria denudata (https:// www. natur epl. com, https:// www. disco verli fe. org) such as actinomycetes, microscopic fungi, and plants. Slime molds types However, the others, such as slime molds, have not Acellular slime molds been taken into account and can be considered unex- Te life cycle of this group of slime molds encompasses plored strains. Terefore, this article has focused on the two strikingly diferent trophic (feeding) stages. Te potential of these creatures as an alternative source of plasmodium structure, consisting of a distinctive multi- antibiotics. nucleate mass, involves as many as 10,000 dividing nuclei without individual cell membranes. Tis color- Slime molds ful protoplasm creeps along in amoeboid fashion over Slime molds are protists with two stages in their life moist, cool, and shaded places, such as within cracks of cycles. In one stage, they behave like protozoa (amoeba) decomposing wood, underneath the partially decayed while acting like fungi in the other. In the protozoan bark of tree trunks and stumps, or other organic mat- phase, they engulf food particles, other microbes and ter in high humidity condition, and in leaf debris on the consuming decaying vegetation. Tese microorganisms forest foor which degrades and feeding by endocytosis are included in two groups: acellular slime molds (Myxo- (Willey et al. 2014; Dembitsky et al. 2005). Te other gastria) and cellular slime molds (Dictyostelium) (Wil- stage of its life cycle starts when plasmodium mass is ley et al. 2014). Recently, slime molds have been known starved or dried. At this time, the plasmodium typically as good resources of natural compounds with bioactiv- diferentiates and develops fruiting bodies containing ity.