3.1. P. aeruginosa efflux pump systems
Gram-negative bacteria possess efflux pump systems composed of an inner membrane transporter, an outer membrane channel, and membrane fusion proteins. Efflux activity does not require a given substrate to accumulate within the periplasmic space, indicating that these compounds are efficiently expelled through the inner and outer membranes (Fig. 1) 13. RND efflux pumps are able to effectively remove antimicrobial compounds from the cytoplasm through this mechanism (Poole 200414; Piddock 200615; Lister et al. 200916. To date, 12 RND-type efflux pump systems have been described for P. aeruginosa, including the MexAB-OprM 17, MexCDOprJ 18, MexEF-OprN 19, MexXY20, MexJK 21, MexGHI-OpmD 22, MexVW-OprM 23, CzcCBA 24, 25, TriABC-OpmH 26, MuxABC-OpmB 27, MexPQOpmE, and MexMN-OprM 28 systems. Given the low permeability of the outer bacterial membrane and the high efficiency of active efflux, these systems are key to the expulsion of antibiotics from these bacteria.
3.2. Global publication trends
3.2.1. Numbers of publications
We identified 2583 total studies published from 1994–2019 that met our search criteria. While 1994 was the first year in which a relevant study was published, the majority of identified studies were published from 2009–2019 (1915, 74.14%), indicating an upward publication trend in this field (Fig. 2b)
3.2.2. Contributions of individual nations
The countries that made the largest contributions to the field of P. aeruginosa research are shown in Fig. 2a. The USA published the largest number of articles in this field (759, 29.38%), followed by the UK (266, 10.30%), China (254, 8.94%), Japan (231, 8.94%), France (221, 8.56%), Canada (173, 6.70%), Spain (151, 5.85%), Germany (111, 4.30%), India(90, 3.48%), and Switzerland (64, 2.48%)(Fig. 2c).
3.3. Publication quality
3.3.1.Total citation frequencies
The overall frequency of research pertaining to P. aeruginosa efflux pumps was 112,062, the total number of citations removed from the citation is 87,308༌the index of the cited article is 52,656, and the citation index for the self-introduction is 50,484, the average citation is The number of times is 46.81 and the h-index is 159. This underscores the rapid developments in the field of P. aeruginosa efflux pump research, and suggests that this is an active and collaborative research field. Publications from the USA exhibited the greatest number of total citations (39,290), followed by Japan (9,569), the UK (9,342), Canada (9,163), France (8,951), Spain (6,504), Germany (4,970), Switzerland (3,462), Denmark (3,383), and Belgium (2,381) (Fig. 3a).
3.3.2. Average citation frequency
Publications from Denmark exhibited the highest average number of citations (89.03), followed by those from the UK (67.21), Canada (64.99), the USA (64.83), Switzerland (62.95), Germany (55.22), Belgium (54.11), Spain (50.42), Japan (49.07), and France (48.12) (Fig. 3b).
3.3.3. H-index values
Average H-index values were highest for relevant studies from the USA (104), followed by those for studies from Japan (52), Canada (51), England (50), France (49), Spain (45), Germany (37), Switzerland (32), Denmark (24), and Belgium (24) (Fig. 3c).
3.4. Bibliographic coupling analysis
We next performed bibliographic coupling analyses to evaluate the similarity relationships between different articles. Bibliographic coupling occurs when a given pair of articles cite a common third article, and serves as an indicator that these studies are focused on related topics.
3.4.1. Journal
A total of 134 journals were identified in this study and were analyzed using VOSviewer (Fig. 4a). The journals with the highest link strength values were, in order, Antimicrobial Agents and Chemotherapy (IF = 4.904, 2019, total link strength = 183,120 times), Journal of Bacteriology (IF = 3.004, 2019, total link strength = 88,379times), Frontiers in Microbiology (IF = 4.235, 2019, total link strength = 78,825 times), The Journal of Antimicrobial Chemotherapy (IF = 5.439, 2019, total link strength = 53,582), PLOS ONE (IF = 2.24, 2018, total link strength = 50,901 times), and Clinical Microbiology Reviews (IF = 20.642 total link strength = 36,328 times).
3.4.2. Institutions
We assessed studies from 173 different research institutions in the present analysis, focusing on institutions with more than five publications (Fig. 4b). The institutions with the highest total link strength values were, in order, Univ Calif Berkeley, Csic, Queens Univ, Univ Oklahoma, and Unic Cambridge (with total link strength values of 107,430, 102,171, 95,375, 75,888, and 62,932 times, respectively).
3.4.3. Countries
We analyzed articles from 74 different countries in this analysis using VOSviewer, focusing specifically on countries with more than five publications (Fig. 4c). The countries with the greatest total link strength values in this analysis were, in order, the USA, France, Japan, Canada, and the UK (with total link strength values of 694,743, 306,153, 299,809, 272,971, and 228,589 times, respectively.
3.5.Co-authorship analysis
3.5.1 Authors
A co-authorship analysis was used to evaluate the linkage strength based upon numbers of co-authored papers. In total, we identified 206 authors with over 5 documents (Fig. 5a). The authors with the greatest total linkage strength values were, as follows, Lee VJ, Lomovskaya O, Nakae T, Nishino Kunihiko, and Nakayama K (with total linkage strength values of 77, 64, 64, 64, and 50, respectively).
3.5.2. Institutions
We identified institutions with over 5 publications (Fig. 5b), and found that the institutions with the greatest total linkage strength values were, as follows, Osaka University, the University of Copenhagen, Colorado State University, Rigshosp, and Csic (with total linkage strength values of 32, 27, 22, 22, and 21, respectively).
3.5.3. Countries
We identified 51 total countries with over 5 publications in this study (Fig. 5c). The countries with the greatest total link strength were the USA, France, the UK, Germany, and Japan (link strength scores of 200, 97, 81, 70, and 64, respectively).
3.6.Co-citation analysis
3.6.1. Authors
A co-citation analysis was conducted based upon the number of times articles were cited together. We identified 867 references with over 20 citations (Fig. 6a). The authors with the greatest total linkage strength values in this analysis were, in order, Poole K, Nikaido H, Li XZ, Lomovskaya O, and Piddock LVJ (with total link strength scores of 66,431, 53,932, 53,887, 36,379, and 30,502 times, respectively).
3.6.2. Journal
Next, a co-citation analysis of 475 identified journals with over 20 citations was conducted (Fig. 6b). The journals with the highest total link strength values were, in order, Antimicrob Agents Chemother, J Bacteriol, J Antimicrob, Mol Microbiol, and P Nat Acad Sci USA (with total link strength scores of 1,489,446, 873,877, 593,826, 379,217, and 329,069 times, respectively.
3.7. Co-occurrence analysis
A co-occurrence analysis was additionally performed with the goal of identifying research directions within this field based upon specific keywords that were used at high frequencies in published studies 29. We specifically focused on keywords that were used five or more times in titles and abstracts, leading to the identification of 651 keywords that we were able to classify into three primary clusters: “Efflux pump resistance mechanism research”, “Multidrug efflux transporter mechanism research”, and “Efflux pump inhibitor research” (Fig. 7a). This suggests that these are primary areas of research interest in the P. aeruginosa efflux pump research field.
We additionally separated these keywords by color based on the frequencies with which they appeared in included publications in a time-dependent fashion, with blue and red keywords corresponding to terms that appeared less recently and more recently, respectively (Fig. 7b). This approach suggested that most research before 2019 was primarily focused on “resistance molecular mechanism research” and “transfer mechanism research”, whereas “inhibitor research” represents a growing area of future research interest.