Efficacy and mechanism of actions of natural antimicrobial drugs

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Abstract

Microbial infections have significantly increased over the last decades, and the mortality rates remain unacceptably high. The emergence of new resistance patterns and the spread of new viruses challenge the eradication of infectious diseases. The declining efficacy of antimicrobial drugs has become a global public health problem. Natural products derived from natural sources, such as plants, animals, and microorganisms, have significant efficacy for the treatment of infectious diseases accompanied by less adverse effects, synergy, and ability to overcome drug resistance. As the Chinese female scientist Youyou Tu received the Nobel Prize for the antimalarial drug artemisinin, antimicrobial drugs developed from Traditional Chinese Medicine are expected to receive increasing attention again. This review summarizes the antimicrobial agents derived from natural products approved for nearly 20 years and describes their efficacy and mode of action. The aim of this unit is to review the current status of antimicrobial drugs from natural products in order to increase the value of natural products as a source of novel drug candidates for infectious diseases.

Introduction

Infectious diseases caused by combinations of bacteria, fungi, viruses, and parasites still cause high global morbidity and mortality (Leeds, Schmitt, & Krastel, 2006). Several surveys indicated that approximately 700,000 annual deaths worldwide are due to antibiotic resistance (O’Neill, 2016; Tagliabue & Rappuoli, 2018). And it is estimated that antimicrobial resistance infectious will cause 10 million deaths every year by 2050 in the world, which is much higher than that of malignant tumors (Bassetti et al., 2017). Additionally, infections contribute to 20% of all human tumors (van Elsland & Neefjes, 2018). The World Health Organization (WHO) describes bacteria as a class I carcinogen (Eyvazi et al., 2020). The number of infected individuals caused by Helicobacter pylori, one of the most common bacterial infections in human beings, was approximately 4.4 billion in 2015 (Hooi et al., 2017). Helicobacter pylori infection is also the main risk factor (accounting for 60–70%) for gastric cancer worldwide (Choi et al., 2020; Fock, 2014). The drug resistance of Helicobacter pylori has reached an alarming level in the world (Savoldi, Carrara, Graham, Conti, & Tacconelli, 2018), and it was considered to be as dangerous as methicillin-resistant Staphylococcus aureus (Dang & Graham, 2017). Meanwhile, invasive fungal infections are associated with at least 1.5 million deaths worldwide each year (Brown et al., 2012; Bassetti et al., 2017). Fungi are eukaryotes, and many potential targets for therapy in humans cause substantial host toxicity risk. Thus, antifungal drug development is challenging. Viral diseases caused by new and re-emerging viruses threaten human health, and the emergence of drug resistance challenge the eradication of viral diseases (Huang, Su, Feng, Liu, & Song, 2014). The WHO conducted surveys from 2014 to 2018 in randomly selected clinics in 18 countries and found that more than 10% of adults infected with HIV are resistant to the backbone of HIV treatment: efavirenz and nevirapine in 12 nations. If treatment delivery is poor or patchy, resistance could increase (Mega, 2019). Natural products derived from natural sources, such as plants, animals, and microorganisms, have been a source of medicinal agents for thousands of years because of their wide variety of biological activities in human, veterinary, and agriculture. An impressive number of modern drugs have been isolated from natural sources because of their use in traditional medicine (Baker, Chu, Oza, & Rajgarhia, 2007; Cragg & Newman, 2001b; Katz & Baltz, 2016). The identification and development of antibacterial agents are historically closely connected with natural products as the ultimate source (or progenitor) of most antibacterial agents in clinical use (Harvey, Edrada-Ebel, & Quinn, 2015; Moloney, 2016; Shen, 2015). Even though the exploration of natural products as a source of new antibiotics has considerably reduced over the past 20 years, natural products have again attracted interest as sources because of current antibacterial drug resistance (Moloney, 2016; Silver, 2015). The natural-based drug discovery has resulted in the development of anti-infectious agents and continues to contribute to new leads in clinical trials (Saklani & Kutty, 2008). Although microbes are the purveyors of a multitude of human maladies, human medicine and disease treatment also owe a great deal to microorganisms because microorganism-derived natural products or their synthetic analogs represent a large proportion of the drugs that are currently in clinical use. Thus, microorganisms play an important role in the production of antibiotics and other drugs for the treatment of serious infectious diseases (Demain, 2014). The discovery of penicillin and its use in the clinic in the 1940s was soon followed by the discovery of a huge number of antibiotics from microbes, particularly actinomycetes and fungi (Dias, Urban, & Roessner, 2012; Hutchings, Truman, & Wilkinson, 2019). The use of herbal drugs is again escalating in the form of complementary and alternative medicine. Herbal remedies play a fundamental role in traditional medicine in China, Korea, Japan, India, and in rural areas of Colombia, where they are often the therapeutic of choice to cure influenza and concomitant infections. With its 5000 years of history, Traditional Chinese Medicine (TCM) continues to provide front-line pharmacotherapy for millions of people worldwide. Natural products, which mainly originates from TCM, has remarkable anti-microbial effect and rarely causes side effects (Ding et al., 2020; Huang et al., 2020; Ren et al., 2018; Zou et al., 2020). Natural drugs derived from Chinese herb not only overcome the resistance but also increase the susceptibility of many non-natural drugs (Liu, Durham, Richards, & Michael, 2000; Hu, Zhao, Hara, & Shimamura, 2001; Perumal, Mahmud, & Mohamed, 2018; Soltani, Fazeli, Bahri Najafi, & Jelokhanian, 2017; Zhang et al., 2020). The Chinese female scientist Youyou Tu received the Nobel Prize in Physiology or Medicine for the antimalarial drug artemisinin. Artemisinin is a natural product derived from the Chinese herb Artemisia annua and has overwhelming antimalarial activity. It is expected to be the most promising candidate compound to ease the worldwide malaria burden (Owens, 2015; Wang et al., 2019). Overall, natural products from microbes and plants make excellent drugs against infectious bacteria, viruses and fungi resistance (Cragg & Newman, 2001a; Di Santo, 2010; Rossiter, Fletcher, & Wuest, 2017; Sencanski et al., 2015) for improved quality of life.

This review summarizes the antimicrobial agents that were derived from natural products and were approved by the US Food and Drug Administration (FDA) from 2000 to 2020 (Fig. 1) and the National Medical Products Administration (NMPA) of China, the former China Food and Drug Administration (CFDA), classified according to their mode of action (Table 1). The chemotaxonomy of the producing organisms and some information relevant for antimicrobial drug pharmacokinetic metabolism are also described (Table 2). Additionally, the natural antimicrobial candidates in the pre-clinical or in the lab were summarized (Supplementary Table S1). The aim of this unit is to review the current status of antimicrobial drugs from natural products in order to increase the value of natural products as a source of novel drug candidates for infectious diseases.

Section snippets

Daptomycin

Daptomycin (CUBICIN®) derived from Streptomyces roseosporus is a cyclic lipopeptide antibacterial. It was the first lipopeptide antibiotic approved by the US FDA (09/2003) in clinical use for the treatment of adult and pediatric patients with complicated skin and skin structure infections (cSSSIs) caused by Gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subsp. equisimilis, and

Caspofungin acetate

Caspofungin acetate (CANCIDAS®) is derived from the fungus Glarea lozoyensis. Its main ingredient, caspofungin, was approved by the US FDA (01/2001) for the treatment of candidemia and the following candida infections: intra-abdominal abscesses, peritonitis, pleural space infections, esophageal candidiasis, and invasive aspergillosis. It is also indicated as empirical therapy for presumed fungal infections in febrile, neutropenic adult, and pediatric patients (Caspofungin FDA label, 2019;

Oseltamivir phosphate

Oseltamivir (TAMIFLU®), the sialic acid analogue, is a neuraminidase inhibitor against influenza A and B viruses (Fig. 2C) (Mendel et al., 1998; Sidwell et al., 1998), and was approved by the US FDA (09/1999) for the treatment of acute, uncomplicated influenza A or B illness in adults and pediatric patients (Oseltamivir FDA Label, 2019). Oseltamivir is recommended for treatment and prophylaxis of illness caused by avian influenza strains, including the highly pathogenic avian influenza A (H5N1)

Andrographolide

Andrographolide, a labdane diterpenoid derived from traditional medicinal herb Andrographis paniculate (commonly known as the “king of bitters”), has been used clinically in China (Fig. 3A). Up to now, dosage forms of andrographolide approved by former CFDA include tablets, soft capsules, and dropping pills. It can relieve the symptoms of inflammation, fever, and pain caused by a wide variety of bacterial infections, including Pseudomonas aeruginosa, S. aureus, Escherichia coli, and

Conclusions and perspectives

The declining efficacy of antimicrobial drugs has become a global public health problem. Such a decline is partly due to inappropriate use of antimicrobial drugs, presence of antibiotics in animal and plant feed, lack of sanitary practices, and variation in the genetic makeup of microbes. Thus, the search for new antibacterial drugs is urgent. Natural products possess a broad spectrum of chemical and functional diversity and serve as the bane of antibiotic resistance, which make them the most

Declaration of Competing Interest

The authors declare that no conflict of interest exists.

Acknowledgements

This work was supported by the Program for Pearl River New Stars of Science and Technology (201906010010), the National Natural Science Foundation of China (81873080) to Y.L., and the Major Scientific and Technological Projects of Guangdong Province (2019B020202002) and Chinese Academy of Traditional Chinese Medicine (ZZ13-035-02, 2019XZZX-LG04) to S. L.

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