Drugs for Superbugs: Antibiotic Discovery, Modes of Action and Mechanisms of Resistance

A special issue of Antibiotics (ISSN 2079-6382).

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 25449

Special Issue Editors

Special Issue Information

Dear Colleagues,

Antibiotics have proven to be powerful drugs for the control of infectious diseases caused by bacteria and remain one of the most significant discoveries in modern medicine. The development of antibiotic resistance is the consequence of decades of constant selective pressure via the underuse, overuse and misuse of therapeutic molecules, which highly benefit the extraordinary genetic capacities of bacteria. The remarkable plasticity of microorganism genomes in addition to the capacity to acquire and transmit genetic determinants of resistance are conserved evolution strategies and have exacerbated the worldwide resistance problem.

The quest for new antibacterials to overcome resistance problems has long been a top research priority. However, scientific difficulties and low financial returns have led to the withdrawal of many pharmaceutical companies from antibiotic R&D. On the other hand, academia is still highly prolific in R&D on antibiotics discovery from the most diverse sources, their modes of action and mechanisms of resistance.

It is our aim that this event can provide an opportunity to representatives of academia, industry and health services to discuss and advance our current knowledge on how to control microorganisms.

We welcome discussions of the following topics at the event:

  • Drug discovery and development—from natural sources to (bio)synthesis;
  • Drug repurposing for antibacterial therapy;
  • Antibiotics recycling and resistance modifiers;
  • Virtual screening;
  • Susceptibility testing;
  • Mechanisms of action;
  • Anti-virulence;
  • Pharmacological parameters, including in vitro or in vivo modelling studies;
  • Novel delivery systems for antibacterials;
  • Mechanisms of resistance—from natural to acquired;
  • Cross-resistance;
  • Omics in antibacterial action and resistance;
  • Epidemiology and the emergence of antibiotic resistant pathogens;
  • Clinical trials and clinical cases of antibiotic resistance;
  • Antibacterials and interfaces.

This Special Issue welcomes both selected papers from the ECA 2022 and the papers that promote and advance the exciting and rapidly changing field.

Submitted contributions will be subjected to peer review and, upon acceptance, will be published with the aim of rapidly and widely disseminating research results, developments, and applications.

We look forward to receiving your contributions.

Dr. Manuel Simões
Dr. Marc Maresca
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antibiotics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (10 papers)

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21 pages, 5687 KiB  
Article
Spiramycin Disarms Pseudomonas aeruginosa without Inhibiting Growth
by Matteo Calcagnile, Inès Jeguirim, Salvatore Maurizio Tredici, Fabrizio Damiano and Pietro Alifano
Antibiotics 2023, 12(3), 499; https://doi.org/10.3390/antibiotics12030499 - 2 Mar 2023
Cited by 4 | Viewed by 1911
Abstract
Spiramycin is a 16-membered macrolide antibiotic currently used in therapy to treat infections caused by Gram-positive bacteria responsible for respiratory tract infections, and it is also effective against some Gram-negative bacteria and against Toxoplasma spp. In contrast, Pseudomonas aeruginosa, which is one [...] Read more.
Spiramycin is a 16-membered macrolide antibiotic currently used in therapy to treat infections caused by Gram-positive bacteria responsible for respiratory tract infections, and it is also effective against some Gram-negative bacteria and against Toxoplasma spp. In contrast, Pseudomonas aeruginosa, which is one of the pathogens of most concern globally, is intrinsically resistant to spiramycin. In this study we show that spiramycin inhibits the expression of virulence determinants in P. aeruginosa in the absence of any significant effect on bacterial multiplication. In vitro experiments demonstrated that production of pyoverdine and pyocyanin by an environmental strain of P. aeruginosa was markedly reduced in the presence of spiramycin, as were biofilm formation, swarming motility, and rhamnolipid production. Moreover, treatment of P. aeruginosa with spiramycin sensitized the bacterium to H2O2 exposure. The ability of spiramycin to dampen the virulence of the P. aeruginosa strain was confirmed in a Galleria mellonella animal model. The results demonstrated that when G. mellonella larvae were infected with P. aeruginosa, the mortality after 24 h was >90%. In contrast, when the spiramycin was injected together with the bacterium, the mortality dropped to about 50%. Furthermore, marked reduction in transcript levels of the antimicrobial peptides gallerimycin, gloverin and moricin, and lysozyme was found in G. mellonella larvae infected with P. aeruginosa and treated with spiramycin, compared to the larvae infected without spiramycin treatment suggesting an immunomodulatory activity of spiramycin. These results lay the foundation for clinical studies to investigate the possibility of using the spiramycin as an anti-virulence and anti-inflammatory drug for a more effective treatment of P. aeruginosa infections, in combination with other antibiotics. Full article
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23 pages, 2958 KiB  
Article
No Chance to Survive: Mo-CBP3-PepII Synthetic Peptide Acts on Cryptococcus neoformans by Multiple Mechanisms of Action
by Tawanny K. B. Aguiar, Felipe P. Mesquita, Nilton A. S. Neto, Francisco Í. R. Gomes, Cleverson D. T. Freitas, Rômulo F. Carneiro, Celso S. Nagano, Luciana M. R. Alencar, Ralph Santos-Oliveira, Jose T. A. Oliveira and Pedro F. N. Souza
Antibiotics 2023, 12(2), 378; https://doi.org/10.3390/antibiotics12020378 - 12 Feb 2023
Viewed by 2206
Abstract
Multidrug-resistant Cryptococcus neoformans is an encapsulated yeast causing a high mortality rate in immunocompromised patients. Recently, the synthetic peptide Mo-CBP3-PepII emerged as a potent anticryptococcal molecule with an MIC50 at low concentration. Here, the mechanisms of action of Mo [...] Read more.
Multidrug-resistant Cryptococcus neoformans is an encapsulated yeast causing a high mortality rate in immunocompromised patients. Recently, the synthetic peptide Mo-CBP3-PepII emerged as a potent anticryptococcal molecule with an MIC50 at low concentration. Here, the mechanisms of action of Mo-CBP3-PepII were deeply analyzed to provide new information about how it led C. neoformans cells to death. Light and fluorescence microscopies, analysis of enzymatic activities, and proteomic analysis were employed to understand the effect of Mo-CBP3-PepII on C. neoformans cells. Light and fluorescence microscopies revealed Mo-CBP3-PepII induced the accumulation of anion superoxide and hydrogen peroxide in C. neoformans cells, in addition to a reduction in the activity of superoxide dismutase (SOD), ascorbate peroxidase (APX), and catalase (CAT) in the cells treated with Mo-CBP3-PepII. In the presence of ascorbic acid (AsA), no reactive oxygen species (ROS) were detected, and Mo-CBP3-PepII lost the inhibitory activity against C. neoformans. However, Mo-CBP3-PepII inhibited the activity of lactate dehydrogenase (LDH) ergosterol biosynthesis and induced the decoupling of cytochrome c (Cyt c) from the mitochondrial membrane. Proteomic analysis revealed a reduction in the abundance of proteins related to energetic metabolism, DNA and RNA metabolism, pathogenicity, protein metabolism, cytoskeleton, and cell wall organization and division. Our findings indicated that Mo-CBP3-PepII might have multiple mechanisms of action against C. neoformans cells, mitigating the development of resistance and thus being a potent molecule to be employed in the production of new drugs against C. neoformans infections. Full article
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20 pages, 3639 KiB  
Article
Evaluation of the Efficiency of Random and Diblock Methacrylate-Based Amphiphilic Cationic Polymers against Major Bacterial Pathogens Associated with Cystic Fibrosis
by Magali Casanova, Hamza Olleik, Slim Hdiouech, Clarisse Roblin, Jean-François Cavalier, Vanessa Point, Katy Jeannot, Baptiste Caron, Josette Perrier, Siméon Charriau, Mickael Lafond, Yohann Guillaneuf, Stéphane Canaan, Catherine Lefay and Marc Maresca
Antibiotics 2023, 12(1), 120; https://doi.org/10.3390/antibiotics12010120 - 8 Jan 2023
Cited by 3 | Viewed by 1868
Abstract
Cystic fibrosis (CF) is associated with repeated lung bacterial infection, mainly by Pseudomonas aeruginosa, Staphylococcus aureus, and Mycobacterium abscessus, all known to be or becoming resistant to several antibiotics, often leading to therapeutic failure and death. In this context, antimicrobial [...] Read more.
Cystic fibrosis (CF) is associated with repeated lung bacterial infection, mainly by Pseudomonas aeruginosa, Staphylococcus aureus, and Mycobacterium abscessus, all known to be or becoming resistant to several antibiotics, often leading to therapeutic failure and death. In this context, antimicrobial peptides and antimicrobial polymers active against resistant strains and less prompt to cause resistance, appear as a good alternative to conventional antibiotics. In the present study, methacrylate-based copolymers obtained by radical chemistry were evaluated against CF-associated bacterial strains. Results showed that the type (Random versus Diblock) and the size of the copolymers affected their antibacterial activity and toxicity. Among the different copolymers tested, four (i.e., Random10200, Random15000, Random23900, and Diblock9500) were identified as the most active and the safest molecules and were further investigated. Data showed that they inserted into bacterial lipids, leading to a rapid membranolytic effect and killing of the bacterial. In relation with their fast bactericidal action and conversely to conventional antibiotics, those copolymers did not induce a resistance and remained active against antibiotic-resistant strains. Finally, the selected copolymers possessed a preventive effect on biofilm formation, although not exhibiting disruptive activity. Overall, the present study demonstrates that methacrylate-based copolymers are an interesting alternative to conventional antibiotics in the treatment of CF-associated bacterial infection. Full article
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19 pages, 2969 KiB  
Article
Photoinactivation of Planktonic Cells, Pseudohyphae, and Biofilms of Candida albicans Sensitized by a Free-Base Chlorin and Its Metal Complexes with Zn(II) and Pd(II)
by Paula V. Cordero, María G. Alvarez, Edwin J. Gonzalez Lopez, Daniel A. Heredia and Edgardo N. Durantini
Antibiotics 2023, 12(1), 105; https://doi.org/10.3390/antibiotics12010105 - 6 Jan 2023
Cited by 1 | Viewed by 1384
Abstract
Invasive candidiasis is an important cause of morbidity and mortality, and its occurrence is increasing due to the growing complexity of patients. In particular, Candida albicans exhibits several virulence factors that facilitate yeast colonization in humans. In this sense, the photodynamic inactivation of [...] Read more.
Invasive candidiasis is an important cause of morbidity and mortality, and its occurrence is increasing due to the growing complexity of patients. In particular, Candida albicans exhibits several virulence factors that facilitate yeast colonization in humans. In this sense, the photodynamic inactivation of yeasts is a promising new alternative to eliminate fungal infections. Herein, the photodynamic activity sensitized by a free-base chlorin (TPCF16) and its complexes with Zn(II) (ZnTPCF16) and Pd(II) (PdTPCF16) was investigated in order to eliminate C. albicans under different forms of cell cultures. A decrease in cell survival of more than 5 log was found in planktonic cells incubated with 5 μM TPCF16 or ZnTPCF16 upon 15 min of white-light irradiation. The mechanism of action mainly involved a type II pathway in the inactivation of C. albicans cells. In addition, the photodynamic action induced by these chlorins was able to suppress the growth of C. albicans in a culture medium. These photosensitizers were also effective to photoinactivate C. albicans pseudohyphae suspended in PBS. Furthermore, the biofilms of C. albicans that incorporated the chlorins during the proliferation stage were completely eradicated using 5 μM TPCF16 or ZnTPCF16 after 60 min of light irradiation. The studies indicated that these chlorins are effective photosensitizing agents to eliminate C. albicans as planktonic cells, pseudohyphae, and biofilms. Full article
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10 pages, 1271 KiB  
Article
Bacterial Isolates from Urinary Tract Infection in Dogs and Cats in Portugal, and Their Antibiotic Susceptibility Pattern: A Retrospective Study of 5 Years (2017–2021)
by Andreia Garcês, Ricardo Lopes, Augusto Silva, Filipe Sampaio, Daniela Duque and Paula Brilhante-Simões
Antibiotics 2022, 11(11), 1520; https://doi.org/10.3390/antibiotics11111520 - 31 Oct 2022
Cited by 14 | Viewed by 2910
Abstract
There are growing concerns regarding the rise of antimicrobial-resistant bacteria in companion animals. This study aimed to bring new insights into the current scenario of Portugal’s antimicrobial resistance bacteria isolated from companion animals with urinary tract infections and is the first to be [...] Read more.
There are growing concerns regarding the rise of antimicrobial-resistant bacteria in companion animals. This study aimed to bring new insights into the current scenario of Portugal’s antimicrobial resistance bacteria isolated from companion animals with urinary tract infections and is the first to be performed during a long period on a large scale. Of a total of 17472 urine samples analyzed, 12,166 (69.6%) (CI 12,200–12,200) were negative for bacterial growth, and 5306 (30.4%) (95% CI 5310–5310) had bacterial growth. Of the culture-positive samples, 5224 (96.6%) (95% CI 5220–5220) were pure cultures and 82 (3.2%) (95% CI 81.9–82.1) had mixed growth. Escherichia coli was the most frequently isolated bacteria (n = 2360, 44.5%) (95% CI 2360–2360), followed by Proteus mirabilis (n = 585, 11%) (95% CI 583–583), Enterococcus faecium (n = 277, 5.2%) (95% CI 277–277) and Staphylococcus pseudintermedius (n = 226, 4.3%) (95% CI 226–226). The overall susceptibility rates were low for erythromycin (45.3%) and clindamycin (51.3%), and high for aminoglycosides (96.3%), carbapenems (92.4%), trimethoprim-sulfamethoxazole (81.2%), and quinolones (79.9%). E. coli also showed considerable resistance to amoxicillin-clavulanic acid. The rates of multidrug-resistant bacteria are still high compared to the northern countries of Europe. This study’s findings show the emergence of antibiotic resistance in the antibiotic agents commonly used in the treatment of UTIs in dogs and cats in Portugal. Full article
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16 pages, 3167 KiB  
Article
Molecular Characterization of Extended Spectrum β-Lactamase (ESBL) and Virulence Gene-Factors in Uropathogenic Escherichia coli (UPEC) in Children in Duhok City, Kurdistan Region, Iraq
by Salwa Muhsin Hasan and Khalid S. Ibrahim
Antibiotics 2022, 11(9), 1246; https://doi.org/10.3390/antibiotics11091246 - 14 Sep 2022
Cited by 4 | Viewed by 2457
Abstract
Background: The presence of extended-spectrum β-lactamase (ESBL)-producing bacteria among uropathogens is significantly increasing in children all over the world. Thus, this research was conducted to investigate the prevalence of E. coli and their antimicrobial susceptibility pattern, and both genes of ESBL-producing E. coli [...] Read more.
Background: The presence of extended-spectrum β-lactamase (ESBL)-producing bacteria among uropathogens is significantly increasing in children all over the world. Thus, this research was conducted to investigate the prevalence of E. coli and their antimicrobial susceptibility pattern, and both genes of ESBL-producing E. coli resistant and virulence factor in UTIs patients among children in Duhok Province, Kurdistan, Iraq. Method: a total of 67 E. coli were identified from 260 urine samples of pediatric patients diagnosed with UTIs aged (0–15 years) which were collected from Heevi Pediatric Teaching Hospital, from August 2021 to the end of February 2022. Result: a high proportion of UPEC infections at ages <5 years and the rates among girls (88%) were significantly higher than those among the boys. A wide variety of E. coli are resistant to most antibiotics, such as Amoxicillin, Ampicillin and Tetracycline, and 64% of them were positive for ESBL. Interestingly, the presence of both the ESBL marker genes (blaTEM, and blaCTX-M) as well as both virulence marker genes (pai and hly) were detected in above 90% of E. coli. Conclusion: the data illustrate an alarming increase in UPEC with ESBL production and the emergence of multidrug-resistant drugs in the early age of children. The public health sectors should further monitor the guidelines of using antibiotics in Kurdistan, Iraq. Full article
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13 pages, 1251 KiB  
Article
A Retrospective Study of Risk Factors, Mortality, and Treatment Outcomes for Infections with Carbapenemase-Producing Enterobacterales in a Tertiary Hospital in Havana, Cuba
by Haiyang Yu, Alberto Hernández González, Gonzalo Estévez Torres, María Karla González Molina, Marcia Hart Casares, Xu Han, Waldemar Baldoquín Rodríguez and Dianelys Quiñones Pérez
Antibiotics 2022, 11(7), 942; https://doi.org/10.3390/antibiotics11070942 - 14 Jul 2022
Cited by 3 | Viewed by 1826
Abstract
(1) Background: The spread of carbapenem-resistant Enterobacterales in hospitals constitutes an important epidemiological and therapeutic problem that especially affects vulnerable patients such as perioperative patients. (2) Methods: We conducted a descriptive, observational, retrospective case-control study of patients infected with carbapenemase-producing carbapenem-resistant Enterobacterales (CP-CRE) [...] Read more.
(1) Background: The spread of carbapenem-resistant Enterobacterales in hospitals constitutes an important epidemiological and therapeutic problem that especially affects vulnerable patients such as perioperative patients. (2) Methods: We conducted a descriptive, observational, retrospective case-control study of patients infected with carbapenemase-producing carbapenem-resistant Enterobacterales (CP-CRE) and carbapenem-susceptible Enterobacterales during the perioperative period in a tertiary hospital. (3) Results: Metallo-β-lactamase was detected in all 124 CRE isolates, with NDM-type carbapenemase being dominant, while 3 isolates coproduced KPC-type enzyme and showed high resistance rates against all antibiotics except colistin (25.2%). By analyzing the risk factors for infection, steroid use (OR: 3.22, p < 0.01), prior use of two or more antibiotics (OR: 4.04, p = 0.01), prior use of broad-spectrum cephalosporins (OR: 2.40, p = 0.04), and prior use of carbapenem (OR: 4.77, p = 0.03) were found to be independent risk factors for CP-CRE infection. In addition, in this study, we observed that the clinical outcomes of bloodstream infections and pneumonia associated with CP-CRE posed higher mortality risks. However, by analyzing the associations between treatment options and mortality, it was found that, in bloodstream infections caused by CP-CRE, colistin-based regimens showed a significant advantage (PR = 0.40, p = 0.03). (4) Conclusions: High mortality is associated with nosocomial infections in the perioperative period caused by carbapenemase-producing Enterobacterales, the dissemination of which in health care settings in Cuba remains a public health challenge. Full article
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15 pages, 1592 KiB  
Article
Self-Medication with Antibiotics: Prevalence, Practices and Related Factors among the Pakistani Public
by Adeel Aslam, Che Suraya Zin, Shazia Jamshed, Norny Syafinaz Ab Rahman, Syed Imran Ahmed, Péter Pallós and Márió Gajdács
Antibiotics 2022, 11(6), 795; https://doi.org/10.3390/antibiotics11060795 - 12 Jun 2022
Cited by 14 | Viewed by 3810
Abstract
Self-medication with antibiotics (SMA) has become considerably common in developing countries, which is a critical factor for driving antibiotic resistance. Individuals involved in SMA generally do not have adequate knowledge regarding the appropriate use, indications and dosage of these drugs. The objective of [...] Read more.
Self-medication with antibiotics (SMA) has become considerably common in developing countries, which is a critical factor for driving antibiotic resistance. Individuals involved in SMA generally do not have adequate knowledge regarding the appropriate use, indications and dosage of these drugs. The objective of the present study was to investigate population SMA practices, knowledge and sociodemographic factors associated with SMA in Islamabad, Pakistan. The study adopted a cross-sectional methodology and data collection was performed through an anonymous, structured and pilot-tested questionnaire, which was interview-administered. Inferential statistics and multivariate logistic regression were performed. Out of 480 participants, 55.6% (n = 267) were male with a mean age of 37.1 ± 10.1 years; the total prevalence of SMA was 32.5%. Ciprofloxacin (42.9%) was the most commonly used antibiotic to treat coughs or colds, a runny nose, flu or sore throat, diarrhea or fevers, which were relevant reasons for SMA. Findings from multivariate logistic regression showed that predictors of SMA were: male gender (95% CI: 0.383–1.005), age (95% CI: 0.317–0.953) and highest level of education (95% CI: 0.961–0.649). Despite reasonable access to healthcare facilities, people are still obtaining antibiotics without prescription, bypassing diagnostic and consultative healthcare services. Thus, the government must implement strict healthcare policies to restrict the sale of antibiotics without prescriptions, while at the same time, targeted public awareness campaigns about the proper use of antibiotics are also required. Full article
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16 pages, 600 KiB  
Article
Antibiotic Use, Incidence and Risk Factors for Orthopedic Surgical Site Infections in a Teaching Hospital in Madhya Pradesh, India
by Kristina Skender, Anna Machowska, Vivek Singh, Varun Goel, Yogyata Marothi, Cecilia Stålsby Lundborg and Megha Sharma
Antibiotics 2022, 11(6), 748; https://doi.org/10.3390/antibiotics11060748 - 31 May 2022
Cited by 1 | Viewed by 2696
Abstract
Orthopedic surgeries contribute to the overall surgical site infection (SSI) events worldwide. In India, SSI rates vary considerably (1.6–38%); however, there is a lack of a national SSI surveillance system. This study aims to identify the SSI incidence, risk factors, antibiotic prescription and [...] Read more.
Orthopedic surgeries contribute to the overall surgical site infection (SSI) events worldwide. In India, SSI rates vary considerably (1.6–38%); however, there is a lack of a national SSI surveillance system. This study aims to identify the SSI incidence, risk factors, antibiotic prescription and susceptibility patterns among operated orthopedic patients in a teaching hospital in India. Data for 1205 patients were collected from 2013 to 2016. SSIs were identified based on the European Centre for Disease Prevention and Control guidelines. The American Society for Anesthesiologists classification system was used to predict patients’ operative risk. Univariable and multivariable backward stepwise logistic regressions were performed. Overall, 7.6% of patients developed SSIs over three years. The most common SSIs causative microorganism was Staphylococcus aureus (7%), whose strains were resistant to penicillin (100%), erythromycin (80%), cotrimoxazole (80%), amikacin (60%) and cefoxitin (60%). Amikacin was the most prescribed antibiotic (36%). Male sex (OR 2.64; 95%CI 1.32–5.30), previous hospitalization (OR 2.15; 95%CI 1.25–3.69), antibiotic prescription during hospitalization before perioperative antibiotic prophylaxis (OR 4.19; 95%CI 2.51–7.00) and postoperative length of stay > 15 days (OR 3.30; 95%CI 1.83–5.95) were identified as significant risk factors. Additionally, preoperative shower significantly increased the SSI risk (OR 4.73; 95%CI 2.72–8.22), which is unconfirmed in the literature so far. Full article
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21 pages, 2544 KiB  
Systematic Review
Worldwide Dissemination of blaKPC Gene by Novel Mobilization Platforms in Pseudomonas aeruginosa: A Systematic Review
by Daniela Forero-Hurtado, Zayda Lorena Corredor-Rozo, Julián Santiago Ruiz-Castellanos, Ricaurte Alejandro Márquez-Ortiz, Deisy Abril, Natasha Vanegas, Gloria Inés Lafaurie, Leandro Chambrone and Javier Escobar-Pérez
Antibiotics 2023, 12(4), 658; https://doi.org/10.3390/antibiotics12040658 - 28 Mar 2023
Cited by 10 | Viewed by 2535
Abstract
The dissemination of blaKPC-harboring Pseudomonas aeruginosa (KPC-Pa) is considered a serious public health problem. This study provides an overview of the epidemiology of these isolates to try to elucidate novel mobilization platforms that could contribute to their worldwide spread. [...] Read more.
The dissemination of blaKPC-harboring Pseudomonas aeruginosa (KPC-Pa) is considered a serious public health problem. This study provides an overview of the epidemiology of these isolates to try to elucidate novel mobilization platforms that could contribute to their worldwide spread. A systematic review in PubMed and EMBASE was performed to find articles published up to June 2022. In addition, a search algorithm using NCBI databases was developed to identify sequences that contain possible mobilization platforms. After that, the sequences were filtered and pair-aligned to describe the blaKPC genetic environment. We found 691 KPC-Pa isolates belonging to 41 different sequence types and recovered from 14 countries. Although the blaKPC gene is still mobilized by the transposon Tn4401, the non-Tn4401 elements (NTEKPC) were the most frequent. Our analysis allowed us to identify 25 different NTEKPC, mainly belonging to the NTEKPC-I, and a new type (proposed as IVa) was also observed. This is the first systematic review that consolidates information about the behavior of the blaKPC acquisition in P. aeruginosa and the genetic platforms implied in its successful worldwide spread. Our results show high NTEKPC prevalence in P. aeruginosa and an accelerated dynamic of unrelated clones. All information collected in this review was used to build an interactive online map. Full article
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