Infections induced by bacterial pathogens are one of the major causes of morbidity and mortality worldwide (Moore, et al., 2017). Antibiotic treatment is undoubtedly one of the indispensable strategies of modern medicine in order to combat infections or microbes, such as in cancer therapy, organ transplantation, management of preterm babies, or major surgeries (Laxminarayan, et al., 2013). The “golden era” of antibiotic discovery was from the 1930s to the 1960s (Nathan and Cars, 2014). Meanwhile, in the middle of the 20th century, antibiotics were considered as the “wonder drug”. At the time, there was optimism that communicable disorders were nearly conquered (Zaman, et al., 2017). Unfortunately, when microbes are exposed to antibiotics, the likelihood of drug resistance elevates (Rogers Van Katwyk et al., 2020). The underuse, overuse and misuse of antibiotics lead to the development of resistant pathogens (Davies and Davies, 2010). Furthermore, antibiotic resistance is a growing threat to human, animal, and environment health due to the emergence, spread, and persistence of multidrug-resistant (MDR) bacteria or “super bugs” (Aslam, et al., 2018). In general, MDR bacteria are resistant to three or more antibiotics; while Mycobacterium tuberculosis strains are extremely resistant to almost all classes of antimicrobials (Subramani, et al., 2017). Ultimately, the discovery of antibiotics has not kept pace with the emergence and development of drug resistant pathogens (Aslam, et al., 2018). A number of important organizations, such as the World Health Organization (WHO), US Centers for Disease Control and Prevention, European Medicines Agency, and World Economic Forum have recognized antibiotic resistance as a global concern (Michael, et al., 2014; Rogers Van Katwyk et al., 2020; Spellberg et al., 2016). It currently threatens tens of millions of lives and poses a major challenge to the global economy and development (Hashem et al., 2022; Rogers Van Katwyk et al., 2020). Consequently, more research and novel sources of antibiotics are urgently needed to overcome resistant problems.

Historically, natural products have played a crucial role in the identification and development of antimicrobial agents (Moloney, 2016). For instance, microbial-derived compounds account for the majority of antibiotic drugs. Decades of purification of antibiotics from microbial sources have identified an estimated 28,000 compounds, about 200 of which have been used directly as drugs. In addition, semi-synthetic improvements to these scaffolds yielded an additional 200–300 drugs, vastly exceeding the number of synthetic antibiotics in clinical use (Wright, 2017). Besides, the phytochemicals of plants are numerous in structure, have few side effects, and most of them have antibacterial activity. As a result, they acquired extra attention in the pharmaceutical industry to enhance the biological activity of existing antibiotics or as a potential source of novel antimicrobial agents active against a variety of pathogens, including MDR bacteria (Jubair, et al., 2021; Salem, et al., 2022). Moreover, β-lactams, tetracycline, macrolides, glycopeptides, lincosamides, sulfonamides, oxazolidinones, and fluoroquinolones are representative classes of antibiotics of the modern era, of which six represent naturally occurring compounds, and only the latter three are obtained entirely by chemical synthesis (Rossiter, et al., 2017). In general, natural-product antibiotics hold a privileged position in this field for the following main reasons: First, they are the products of millions of years of evolution. Through natural selection, they interact with cellular targets with high selectivity and efficiency and avoid drug resistance. Next, unlike numerous synthetic molecules, they are products of evolution that have inherent physicochemical properties necessary to penetrate bacterial cells. Finally, molecular selectivity is a hallmark of a large number of naturally occurring antibiotics, resulting in relatively little widespread toxicity (Wright, 2017).

Scientometrics is the quantitative analysis of bibliographic information using mathematical and statistical approaches. It is usually used to identify overall knowledge frameworks, assess current conditions, and predict future research directions in a certain field (Bornmann and Leydesdorff, 2014; de Castilhos Ghisi et al., 2020). In addition, it can be used to compare the contributions of different countries, institutions, journals, and authors (Ke, et al., 2020). Currently, various visualization tools, such as VOSviewer, CiteSpace, and HistCite have been developed to create knowledge maps and are widely used in multiple scientific research fields, including the medical field (Chen, et al., 2021; Huang, et al., 2021). Given the emergence of MDR bacteria and the importance of natural products in antibiotic drug discovery, numerous studies have been performed in recent years (Hashem and Salem, 2022; Moore, et al., 2017; O’Connell, et al., 2013; Rossiter, et al., 2017). However, as far as we know, no scientometric studies have been reported so far. In view of this, we conducted a scientometric analysis of the antimicrobial activity of natural products against MDR bacteria over a 25-year period from 1997 to 2021. The objective of this study was to identify the major contributors and their collaborative networks, including countries, institutions, and authors, as well as influential journals and references. Additionally, major research clusters, hot topics, and emerging trends in this field are explored.

According to the data of the WOS Core Collection database from 1997 to 2021, a total of 1,267 publications in 5 languages were retrieved, and the cumulative number of citations was 34,719. With the prevalence of bacterial resistance issues, studies on the antimicrobial activity of natural products against MDR bacteria has generated considerable exploratory interest, whether in terms of annual published documents or citation counts. Among the 95 countries/Regions involved in the publication of studies in this field, India was the most productive country. The United States ranked second in the total number of publications; however, it was the leading country in the total number of citations. Furthermore, the United States was the most active country in international cooperation and had close collaborations with India, China, Germany and Canada. In addition, China, India, Saudi Arabia, and Germany demonstrated active international cooperation as well. Therefore, combined with the quality and quantity of publications and international cooperation, the United States and India were dominant in this research field. In terms of institutional contribution, the University of Dschang had the largest output. As for the institution co-authorship analysis, the Regional University of Cariri, Federal University of Paraiba, Universidade Federal do Piaui, University of Dschang, and University of Porto showed active cooperation.

To some extent, the number of scientific papers published by an author in a certain field represents his contribution and activity in that field (Wu, et al., 2021b). Most researchers published only one or two papers, meaning that only a handful of authors made sustained contributions to the field. Three authors published more than 10 articles, namely Coutinho HDM, Kuete V and Gibbons S, with 33, 31 and 12 papers respectively. As for author co-authorship analysis, from the perspective of centrality, Coutinho HDM was located at a central position of the cooperating clusters. In author co-citation analysis, combined with the values of co-citations and TLS, Kuete V, Gibbons S and WHO were prominent in this field. Overall, the above results indicated that Coutinho HDM, Kuete V, and Gibbons S made significant contributions in this field. Based on the journal analysis, all papers included in this study were published in 505 journals. Among them, Frontiers in Microbiology (6.064, Q1), Molecules (4.927, Q2), BMC Complementary and Alternative Medicine (2.838, Q2), Antibiotics-Basel (5.222, Q1), and Marine Drugs (6.085, Q1) published the most paper in this research field. In addition to the number of publications, citation frequency is often considered as an important indicator to evaluate the influence of a journal (Wu, et al., 2021b). In the journal co-citation network graph, Antimicrobial Agents and Chemotherapy had the highest co-citations, followed by Journal of Natural Products, Journal of Antimicrobial Chemotherapy, Journal of Bacteriology, Journal of Ethnopharmacology, and Proceedings of the National Academy of Sciences of the United States of America. In general, there is a high probability that future achievements in the field will be published in the listed journals.

The top 10 highly cited papers were published between 1997 and 2017, with six published before 2010. In terms of research content, most of the top 10 most cited papers focused on the discovery of new antibiotics, especially natural product antibiotics of plants and natural products of plants were the primary source. The paper with the highest cited times, written by Fischbach and Walsh (2009) was published in Science, with 1,227 citations. It noted out that methods of new scaffold discovery, such as mining under-explored microbial niche for natural products, were promising approaches against MDR pathogens. The second most cited article was published in Current Opinion in Biotechnology by Daglia (2012). It discussed the synergistic effect of polyphenols in combination with conventional antibiotics against clinical MDR microorganisms. The research topics of five other papers also focused on the antibacterial activity of natural products of plant origin (Ahmad and Beg, 2001; Gibbons, 2004; Al-Zoreky, 2009; Ghosh, et al., 2012; Gopinath, et al., 2012), including two papers on synthesis of silver nanoparticles. The most recent article published in Nature with 402 citations. Richter et al. (2017) predicted compound accumulation rules in bacteria to aid in the discovery and development of novel antibacterial agents against Gram-negative bacteria. Co-cited references are documents in which two publications are cited together by other publications so that they can be considered as the background and foundation of research in a particular field (Ke, et al., 2020). Overall, the top 10 co-citations were focused on the following subjects: antibacterial activity of plant-derived natural products (Cowan, 1999; Kuete, 2010; Stermitz, et al., 2000); antibiotic discovery (efflux pump or cell wall inhibitors) (Ling, et al., 2015; Newman and Cragg, 2016; Stavri et al., 2007); antibiotic resistance (Davies and Davies, 2010); antibacterial discovery process, achievements, and challenges (Payne, et al., 2007); and MIC determination method (Eloff, 1998).

Keyword co-occurrence analysis is commonly used to highlight the frequently occurring keywords that can reveal the subject content and provide a reasonable description of the knowledge structure (Wu et al., 2021b). Meanwhile, the current hot topics and future directions can also be revealed (Guo et al., 2021). The analysis demonstrated that “medicinal plants”, “methicillin-resistant Staphylococcus aureus”, “Staphylococcus aureus”, “biofilm”, “MIC”, and “efflux pumps” were the most commonly used keywords in order, so these terms are presumed to be the hot spots in this field. Combining the formed clusters and all co-occurring keywords, among the related clusters of “MDR bacteria”, methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa (Tasneem et al., 2022), Mycobacterium tuberculosis (Li et al., 2022), and Escherichia coli (Szmolka and Nagy, 2013) were the most frequently mentioned strains. In addition, Acinetobacter baumannii (Borges Duarte and Gonçalves Rodrigues, 2022) and Klebsiella pneumoniae (Ali et al., 2022) could be found in the co-occurring keywords. In “mechanism for inhibiting MDR” theme, suppression of the efflux pump was the primary mechanism studied (Nikaido, 2009). Moreover, anti-biofilm action was also a focus mechanism (Hathroubi, et al., 2017; Mishra, et al., 2020). As for “natural product sources and components” theme, medicinal plant-derived compounds gained significant attention as potential sources of new antimicrobial agents to combat MDR bacteria (Subramani et al., 2017). Besides, actinomycetes and marine natural products were also vital sources (Hou, et al., 2019; Jagannathan, et al., 2021; Zhu, et al., 2014). The notable active components were flavonoids (Song, et al., 2022), alkaloids and phenolics (Suganya, et al., 2022). Essential oil (Badescu, et al., 2022), polyphenols (Jubair, et al., 2021), and berberine (Yu, et al., 2005) were also included in the co-occurrence keywords. In “natural product development approach” theme, biosynthesis of nanoparticles, especially silver nanoparticles, had attracted much attention in order to develop new antibiotics (Anjum and Abbasi, 2016; Alavi, et al., 2022a; Alavi, et al., 2022b; Majoumouo, et al., 2019). Additionally, molecular docking was an impactful technology in drug design in this field (Miryala, et al., 2021). From the overlay visualization map, recent studies mainly focused on the theme of “natural product development approach”. Furthermore, the results showed that keywords such as “Pseudomonas aeruginosa”, “nanoparticles”, “green synthesis”, “antimicrobial peptides”, “antibiofilm”, “antibiofilm activity”, “biosynthetic gene clusters”, and “molecular dynamics simulation” had the latest average appearance year, indicating that these topics may become the research direction in the next few years.

In addition, the main limitations of our analysis are as follows: First, we only searched in the WOS database, and not in other databases such as PubMed, Embase, or Scopus. Therefore, the comprehensiveness of the data will be deficient to some extent. Second, we did not include relevant papers in 2022 because the data of this year are not yet complete enough to complete certain annual data comparison. As a result, some of the latest research progress may be missed. Third, all data in this study were extracted by software, unlike systematic reviews that are manually extracted by two or more independent authors. In consequence, the data used to derive the results in this paper may be biased.

With the prevalence of bacterial resistance problems, interest in the antimicrobial activity of natural products against MDR bacteria has exploded during the past decades. In this study, the current research status and emerging global trends in this field were visualized using a scientometric method. A total of 1,267 related documents including 1,005 original articles and 262 reviews in a period from 1997 to 2021 were retrieved. India is the country with the most output, and the United States is the country with the highest total citations and the most active in international cooperation. The University of Dschang from Cameroon produced the most publications. Coutinho HDM, Kuete V, and Gibbons S had significant influence in this field, as they published a large number of articles and were co-cited in several more publications. Frontiers in Microbiology and Antimicrobial Agents and Chemotherapy were major journals with the highest number of publications and co-citations, respectively. Fischbach and Walsh published the most cited paper in Science with 1,227 citations. The content of most of the top 10 most cited papers focused on the discovery of new antibiotics, especially plant-derived natural product antibiotics. Based on keywords co-occurrence analysis, “medicinal plants”, “methicillin-resistant Staphylococcus aureus”, “Staphylococcus aureus”, “biofilm”, “MIC”, and “efflux pumps” were the most frequently used keywords, so these terms are presumed to be the current hot topics. All selected keywords could be roughly divided into four main themes: “MDR bacteria”, “mechanism for inhibiting MDR”, “natural product sources and components”, and “natural product development approach”, of which the last theme had attracted much attention in recent years. Methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Mycobacterium tuberculosis, and Escherichia coli were the most commonly studied MDR strains, followed by Acinetobacter baumannii and Klebsiella pneumoniae. Inhibition of the efflux pump and anti-biofilm action were the primary mechanism for suppressing MDR. Medicinal plant-derived compounds such as flavonoids, alkaloids, and phenolics were important sources of novel antimicrobial agents against MDR bacteria, followed by actinomycetes and marine natural products. Besides, biosynthesis of nanoparticles, especially silver nanoparticles, was a new strategy to develop highly effective antibacterial agents. Molecular docking was also an important method in this field. Moreover, keywords such as “Pseudomonas aeruginosa”, “nanoparticles”, “green synthesis”, “antimicrobial peptides”, “antibiofilm”, “antibiofilm activity”, “biosynthetic gene clusters”, and “molecular dynamics simulation” had the latest average appearance year, indicating that these topics may become the research hot spots in the coming years. Overall, this study performed a scientometric analysis of the antibacterial activity of natural products against MDR bacteria from a holistic perspective. We hope it can provide an effective reference for the research points and future trends, not only for researchers already working in this field, but also for new researchers interested in this field.