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    Intervention Strategies Using Antimicrobial Peptides

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    The emergence of multidrug-resistant H. pylori poses a public healthcare threat, particularly in low- and middle-income countries. Recently, the World Health Organization has classified clarithromycin-resistant H. pylori as high priority in the research and discovery of novel antibiotics. This study was aimed to systematically review the prevalence of primary antibiotic resistance in H. pylori in Southeast Asian countries (SEAC) and to review current studies of antimicrobial peptides against H. pylori. We systematically searched through electronic databases of studies conducted on antimicrobial resistance of H. pylori in SEA countries. Furthermore, we searched articles that conducted studies on antimicrobial peptides, naturally occurring host’s defense molecules, against H. pylori. After a series of screening processes, 15 studies were included in our systematic review. Our analysis revealed that primary resistance of H. pylori to metronidazole, clarithromycin, and levofloxacin were high in SEAC, although the primary resistance to amoxicillin and tetracycline remains low. Multidrug-resistant H. pylori are emerging in SE Asian countries. The antimicrobial peptides show promising antibacterial and antibiofilm activity against drug-resistant H. pylori. The research and discovery of antimicrobial peptides against H. pylori in SEAC will help in limiting the spread of antimicrobial resistance of H. pylori. 

    1. Introduction

    Helicobacter pylori is one of the most common infectious disease agents worldwide, with more than 50% of the world’s population being infected with this pathogen, mostly in developing countries [1]. Transmission of H. pylori is still uncertain, but several studies have shown that close contact of a mother with a child during childhood is the main transmission route, apart from drinking contaminated water [2]. Since its discovery by Warren and Marshall almost three decades ago, it is now established that this bacterium orchestrates gastric carcinogenesis by producing multiple virulence factors that lead to peptic ulcer and gastric cancer [3]. Gastric cancer is still one of the most common cancers globally, with more than 1 million new cases reported yearly, leading to 768,793 deaths in 2020 alone [4]. Furthermore, gastric cancer patients are mainly detected at the advanced stage of cancer, where cancer prognosis is worse than that of detection at an early stage [5]. A high economic and mortality burden is associated with gastric cancer, with most cases occurring in developing countries where medical resources for early screening and patient management are limited [4]. Therefore, early screening of gastric cancer for detecting precancerous lesions for better prognosis and eradicating H. pylori are two essential strategies to prevent gastric cancer development.
    Treatment of H. pylori includes administering proton pump inhibitors (PPI) coupled with multiple antibiotics through several treatment regimens. In the first-line triple therapy, PPI is administered with amoxicillin and clarithromycin. However, in areas where the clarithromycin resistance rate is higher than 15%, triple therapy containing metronidazole or bismuth-containing quadruple therapy is recommended [6]. Nevertheless, the increasing rate of multiple-drug-resistant H. pylori has implications for the eradication of bacteria to prevent gastric diseases, including gastric cancer and ulcers [7]. The World Health Organization (WHO) has declared clarithromycin-resistant H. pylori a high priority in the research and development of novel antimicrobial discovery [8]. As such, an alarming concern of the increasing rate of antibiotic resistance presents urgency for the discovery of novel or alternative therapies for H. pylori. SEAC are home to more than 650 million people with diverse ethnicities and cultures. Most of these countries are mainly low-and middle-income countries, where medical resources are limited [9]. However, it is also home to diverse natural flora and fauna, with more than 20% of global plant and animal species, and where four out of twenty-five global biodiversity hotspots are found [10]. Antimicrobial peptides (AMP) are a small class of peptides that are part of an organism’s innate immunity with an inhibitory effect against pathogens such as the inhibition of nucleotide and protein synthesis of pathogens, formation of the pore at the cell membrane, and the host’s immunomodulation [11]. AMPs are good candidates for alternative therapies for the treatment of antibiotic-resistant infections and are broad-spectrum antimicrobial agents to which most bacteria evolution is slow. AMP has been isolated from multiple flora and fauna such as amphibians, fish, and plants [12]. Given that SEA has one of the world’s greatest biodiversity hotspots, this region can be one in which AMP research and discovery can be conducted rapidly.

    2. A Review on Intervention Strategy Using AMP

    Given the high resistance rates of H. pylori to critically important antibiotics in this region, we searched the database on intervention strategies of H. pylori treatment using AMP. AMPs are small peptides that have been demonstrated to possess broad-spectrum activity against bacteria. They are usually isolated from natural sources such as the skin of amphibians and venoms. The SEACs are a region with high biological diversity and lush tropical forests where the sources for discovery and research on novel antimicrobial drugs against H. pylori can be further explored. As such, we aimed to summarize the studies conducted on AMPs against H. pylori for understanding the current progress in research. Table 1 summarizes the studies conducted on AMPs against H. pylori. We found that all the studies conducted demonstrated antibacterial activity of AMPs against H. pylori and all studies employed synthetically synthesized AMPs (Table 1). Five AMPs, namely cathelicidin [13], bicarinalin [14], odorranain-HP [15], tilapia Piscidin 4 [16], and pleurain-A [17], were initially identified from natural sources and then synthesized synthetically in the laboratory. Notably, some AMPs, including cathelicidin-like AMP [18], bicarinalin [14], fusion human neutrophil peptide 1 [19], and epinecidin 1 [20], showed bactericidal activity against drug-resistant H. pylori. In addition, cathelicidin from humans and mice exhibited antibiofilm activity against H. pylori and protected the animal model from inflammation induced by H. pylori [13]. A study conducted by Jiang et al. [18] found that a cathelicidin-like peptide, namely Cbf-K16, reduced intercellular and intracellular activity of H. pylori and decreased H. pylori colonization in animal model. Furthermore, helix-coil conformation transitional antimicrobial polypeptides demonstrated bactericidal activity against H. pylori at low pH, suggesting its potential for use in human. Besides that, the peptide demonstrated low toxicity in animal study and an examined stomach, suggesting that the peptide is worthy to be evaluated in clinical trials [21].
    Table 1. Summary of studies conducted on antimicrobial peptides against H. pylori.
    Author Year Name of AMP Source Finding on Antibacterial Activity against H. pylori Reference
    Zhang et al. 2016 Cathelicidin Mouse and human Bactericidal activity against clarithromycin-resistant H. pylori; anti-biofilm activity against H. pylori SS1 strain; protected mouse from H. pylori orchestrated inflammation and reduced H. pylori colonization [13]
    Guzman et al. 2018 Bicarinalin Synthetically synthesized in lab (anti venom Tetramorium bicarinatum) Perturbation of membrane permeability against drug-resistant H. pylori [14]
    Chen et al. 2007 Odorranain-HP Synthetically synthesized in lab (Diskless odorous frog, Odorrana graham) Showed antimicrobial activity against H. pylori (MIC of 20 µg/mL) [15]
    Narayana et al. 2015 Tilapia Piscidin 4 (TP4) Synthetically synthesized in lab (Nile tilapia, Oreochromis niloticus) Demonstrated potential lytic activity against H. pylori surface membrane; disrupted the bacterial cell membrane [16]
    Wang et al. 2007 Pleurain-A Synthetically synthesized in lab (Yunnan frog, Rana pleuraden) Inhibited growth of H. pylori in vitro (30 µg/mL) [17]
    Jiang et al. 2020 Cbf-K16(cathelicidin-like AMP) Synthetically synthesized Demonstrated bactericidal activity against clarithromycin- and amoxicillin-resistant H. pylori; reduced intercellular and intracellular drug-resistant H. pylori in cell culture; showed increased membrane permeation in drug-resistant H. pylori [18]
    Zhang et al. 2018 Fusion human neutrophil peptide 1 Expression system in yeast Eradication of wild type and drug-resistant H. pylori in animal model [19]
    Narayana et al. 2015 Epinecidin-1 Synthetically synthesized in lab Showed bactericidal activity against drug-resistant H. pylori and modulated immune response in mouse-infected H. pylori for bacterial clearance [20]
    Xiong et al. 2017 Helix–coil conformation transitional
    antimicrobial polypeptides
    Synthetically synthesized in lab Displayed bactericidal activity against H. pylori at low pH, both in vitro and in vivo [21]
    Zhang et al. 2015 Pexiganan Synthetically synthesized in lab Inhibited the growth of H. pylori (MIC = 4 µg/mL); decreased H. pylori colonization in animal model [22]
    Zhang et al. 2017 Fusion PGLa-AM1 Synthetically synthesized in lab Showed bactericidal activity against H. pylori in vitro and clearance of the bacteria in vivo [23]
    Makobongo et al. 2012 C12K-2β12 Synthetically synthesized in lab Ruptured H. pylori surface membrane for bactericidal effect; reduced colonization of H. pylori in gerbil model [24]
    Rigano et al. 2012 Tomato defensin Synthetically synthesized in lab Showed antibacterial activity against H. pylori at MIC: 15 µg/mL [25]
    Iwahori et al. 1997 Magainin 2 analog Synthetically synthesized in lab Inhibited growth of H. pylori in vitro [26]
    Abbreviations: AMP: Antimicrobial peptide; MIC: Minimum inhibitory concentration.

    This entry is adapted from 10.3390/antibiotics10091061


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