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Antibiotics Resistance in Gram-Negative Bacteria, 2nd Edition

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

Deadline for manuscript submissions: 15 May 2025 | Viewed by 12350

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Prof. Dr. Simone Simionatto

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Laboratório de Pesquisa em Ciências da Saúde, Universidade Federal da Grande Dourados-UFGD, Dourados, Mato Grosso do Sul, Brazil
Interests: antibiotic resistance; molecular epidemiology of Gram-negative bacteria; antimicrobial effects of natural products on bacteria; antisense therapy; drug repositioning
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Dear Colleagues,

Antimicrobial resistance has been recognized as one of the most serious global threats to human health. The ability of Gram-negative bacteria to acquire resistance to antimicrobials via horizontal gene transfer and mutation is a real threat and a burden on human health and the economy. Even though they are most commonly detected in hospital settings, multi-drug-resistant Gram-negative bacteria have also been described in other ecological niches. The epidemiology of Gram-negative bacteria is complex and the importance of an integrated surveillance system based on the One-Health approach has been widely recognized. The use of antimicrobials in medicine, agriculture and livestock has favored the selection of these pathogens. In addition, increased hospitalization and the indiscriminate use of antimicrobials during the COVID-19 pandemic may have contributed to increased rates of multi-drug-resistant Gram-negative bacteria. Thus, the effects of antimicrobial resistance on public health and the economy in the short and medium term are concerning. Efforts must be taken to implement new policies and control programs on how to use and dispense antibiotics. Furthermore, understanding the resistance mechanisms and epidemiology of bacteria is critical for the development of novel antibacterials, which are needed to meet future demands. This Special Issue seeks manuscript submissions that further our understanding of the epidemiology and antimicrobial resistance of Gram-negative bacteria. Submissions on the search for new drugs developed through structural modification agents, the production of synthetic derivatives or repositioning are especially encouraged.

Prof. Dr. Simone Simionatto
Guest Editor

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Keywords

antimicrobial resistance
epidemiology
genomics surveillance
One-Health
enterobacteriaceae
repurposing
bacteriophages
antimicrobial peptides
natural compounds
virulence profiles

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Published Papers (7 papers)

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Research

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24 pages, 3297 KiB

Open AccessArticle

7-O-Carboxylic Acid-Substituted 3-O-Alkyl Difluoroquercetin; An Aztreonam-Potentiating Agent Against Carbapenemase-Producing Pseudomonas aeruginosa Through Simultaneous Inhibition of Metallo-β-Lactamase and Efflux Pump

by Seongyeon Lee, Taegum Lee, Mi Kyoung Kim, Joong Hoon Ahn, Seri Jeong, Ki-Ho Park and Youhoon Chong

Antibiotics 2024, 13(12), 1202; https://doi.org/10.3390/antibiotics13121202 - 10 Dec 2024

Viewed by 361

Abstract

Background/Objectives: Previously, we reported that 3-O-alkyl difluoroquercetins (di-F-Q) potentiates the antimicrobial activity of aztreonam (ATM) against metallo-β-lactamase (MBL)-producing P. aeruginosa through simultaneous inhibition of MBLs and efflux pumps. However, the ATM-potentiating activity of the 3-O-alkyl di-F-Q was observed only at high and potentially toxic concentrations (32 mg/L). Methods: As both MBLs and efflux pumps reside in the periplasm of Gram-negative bacteria, their inhibitors should accumulate in the periplasmic space. However, the outer membrane porins, the major entry pathway in Gram-negative bacteria, allow the passive diffusion of hydrophilic polar molecules across the outer membrane. Thus, we reasoned that the introduction of a polar substituent at 7-OH position of 3-O-alkyl di-F-Q would enhance its periplasmic concentration to result in potentiation of ATM at lower concentrations. Results: The title compound 5 exhibited inhibitory activity against NDM-1 as well as the efflux pump of P. aeruginosa, which resulted in synergistical potentiation of ATM. A combination of ATM (8 mg/L) and 5 (8 mg/L) inhibited 80% of the ATM-resistant CPPA, while ATM alone did not show any inhibition. In addition, only 4 mg/L of 5 was needed to reduce the MIC₉₀ of ATM four-fold in ATM-resistant CPPA (n = 15). The time–kill data further supported the effectiveness of the combined treatment of ATM with 5, and the combination of ATM (1xMIC) with 8 mg/L of 5 showed bactericidal effects in every bacterial strain tested (PA-002, bla_IMP, PA-003, bla_VIM, PA-014, bla_GES, and PA-017, bla_NDM) by reducing the bacterial loads by 5.1 log₁₀~8.9 log₁₀. Conclusions: The title compound 5 exhibited inhibitory activity against NDM-1 as well as the efflux pump of P. aeruginosa, and the combined inhibitory activity resulted in synergistical potentiation of ATM. It should be noted that most CPPA isolates tested were sensitized to 8 mg/L of ATM upon combination with 4~8 mg/L of 5. Full article

(This article belongs to the Special Issue Antibiotics Resistance in Gram-Negative Bacteria, 2nd Edition)

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20 pages, 5234 KiB

Open AccessArticle

Novel Variant of New Delhi Metallo-Beta-Lactamase (bla_NDM-60) Discovered in a Clinical Strain of Escherichia coli from the United Arab Emirates: An Emerging Challenge in Antimicrobial Resistance

by Farah Al-Marzooq, Akela Ghazawi, Mushal Allam, Timothy Collyns and Aqeel Saleem

Antibiotics 2024, 13(12), 1158; https://doi.org/10.3390/antibiotics13121158 - 2 Dec 2024

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Abstract

Background/Objectives: Carbapenem resistance poses a significant health threat. This study reports the first detection and characterization of a novel variant of New Delhi metallo-β-lactamase (bla_NDM-60) in Escherichia coli from the United Arab Emirates (UAE), including its genetic context and relationship to global strains. Methods: NDM-60-producing E. coli was isolated from a rectal swab during routine screening. Characterization involved whole-genome sequencing, antimicrobial susceptibility testing, and comparative genomic analysis with 66 known NDM variants. Core genome analysis was performed against 42 global E. coli strains, including the single other reported NDM-60-positive isolate. Results: The strain demonstrated extensive drug resistance, including resistance to novel β-lactam/β-lactamase inhibitor combinations, notably taniborbactam. NDM-60 differs from the closely related NDM-5 by a single amino acid substitution (Asp202Asn) and two amino acid substitutions (Val88Leu and Met154Leu) compared to NDM-1. NDM-60 is located on a nonconjugative IncX3 plasmid. The strain belongs to sequence type 940 (ST940). Phylogenetic analysis revealed high diversity among the global ST940 strains, which carry a plethora of resistance genes and originated from humans, animals, and the environment from diverse geographic locations. Conclusions: NDM-60 emergence in the UAE represents a significant evolution in carbapenemase diversity. Its presence on a nonconjugative plasmid may limit spread; however, its extensive resistance profile is concerning. Further studies are needed to determine the prevalence, dissemination, and clinical impact of NDM-60. NDM evolution underscores the ongoing challenge in managing antimicrobial resistance and the critical importance of vigilant molecular surveillance. It also highlights the pressing demand to discover new antibiotics to fight resistant bacteria. Full article

(This article belongs to the Special Issue Antibiotics Resistance in Gram-Negative Bacteria, 2nd Edition)

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15 pages, 2762 KiB

Open AccessArticle

Investigating the Antimicrobial Potential of 560 Compounds from the Pandemic Response Box and COVID Box against Resistant Gram-Negative Bacteria

by Rita de Cássia Cerqueira Melo, Aline Andrade Martins, Andressa Leite Ferraz Melo, Jean Carlos Pael Vicente, Mariana Carvalho Sturaro, Julia Pimentel Arantes, Luana Rossato, Gleyce Hellen de Almeida de Souza and Simone Simionatto

Antibiotics 2024, 13(8), 723; https://doi.org/10.3390/antibiotics13080723 - 1 Aug 2024

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Abstract

Antimicrobial resistance (AMR) has emerged as a significant threat to public health, particularly in infections caused by critically important Gram-negative bacteria. The development of novel antibiotics has its limitations, and therefore it is crucial to explore alternative strategies to effectively combat infections with resistant pathogens. In this context, the present study investigated the antibacterial potency of 560 compounds against the multidrug-resistant (MDR) strains of Klebsiella pneumoniae and Serratia marcescens. The evaluated compounds were selected from the Pandemic Response Box (PRB) and COVID Box (CB) and subjected to assays to determine the inhibitory concentration (IC), minimum bactericidal concentration (MBC), and biofilm formation. Further, the effects of these compounds on membrane integrity were assessed through protein quantification. Several of the evaluated compounds, including fusidic acid, MMV1580853, and MMV1634399, exhibited a significant reduction in biofilm formation and growth in K. pneumoniae. Trimethoprim exhibited potential against S. marcescens. The IC values of the compounds indicated significant microbial growth inhibition at various concentrations. These findings underscore the potency of the existing antibiotics and novel compounds in combating the MDR strains of bacteria. The importance of reconsidering the known antibiotics and utilizing drug repositioning strategies to address the increasing risk of AMR is highlighted. Full article

(This article belongs to the Special Issue Antibiotics Resistance in Gram-Negative Bacteria, 2nd Edition)

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19 pages, 1128 KiB

Open AccessArticle

Analyses of Extended-Spectrum-β-Lactamase, Metallo-β-Lactamase, and AmpC-β-Lactamase Producing Enterobacteriaceae from the Dairy Value Chain in India

by Tushar Kumar Dey, Johanna Frida Lindahl, Åke Lundkvist, Delia Grace, Ram Pratim Deka, Rajeswari Shome, Samiran Bandyopadhyay, Naresh Kumar Goyal, Garima Sharma and Bibek Ranjan Shome

Antibiotics 2023, 12(9), 1449; https://doi.org/10.3390/antibiotics12091449 - 14 Sep 2023

Cited by 2 | Viewed by 2394

Abstract

The consumption of milk contaminated with antibiotic-resistant bacteria poses a significant health threat to humans. This study aimed to investigate the prevalence of Enterobacteriaceae producing β-lactamases (ESBL, MBL, and AmpC) in cow and buffalo milk samples from two Indian states, Haryana and Assam. A total of 401 milk samples were collected from dairy farmers and vendors in the specified districts. Microbiological assays, antibiotic susceptibility testing, and PCR-based genotyping were employed to analyze 421 Gram-negative bacterial isolates. The overall prevalence of β-lactamase genes was 10% (confidence interval (CI) (7–13)), with higher rates in Haryana (13%, CI (9–19)) compared to Assam (7%, CI (4–11)). The identified β-lactamase genes in isolates were bla_CMY, bla_MOX, bla_FOX, bla_EBC, and bla_DHA, associated with AmpC production. Additionally, bla_CTX-M1, bla_SHV, and bla_TEM were detected as ESBL producers, while bla_VIM, bla_IMP, bla_SPM, bla_SIM, and bla_GIM were identified as MBL producers. Notably, Shigella spp. were the dominant β-lactamase producers among identified Enterobacteriaceae. This study highlights the presence of various prevalent β-lactamase genes in milk isolates, indicating the potential risk of antimicrobial-resistant bacteria in dairy products. The presence of β-lactam resistance raises concern as this could restrict antibiotic options for treatment. The discordance between genotypic and phenotypic methods emphasizes the necessity for comprehensive approaches that integrate both techniques to accurately assess antibiotic resistance. Urgent collaborative action incorporating rational and regulated use of antibiotics across the dairy value chain is required to address the global challenge of β-lactam resistance. Full article

(This article belongs to the Special Issue Antibiotics Resistance in Gram-Negative Bacteria, 2nd Edition)

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18 pages, 12522 KiB

Open AccessArticle

Comparative Transcriptomic Profiling of Pellicle and Planktonic Cells from Carbapenem-Resistant Acinetobacter baumannii

by Heng Kang Ng, Suat Moi Puah, Cindy Shuan Ju Teh, Nuryana Idris and Kek Heng Chua

Antibiotics 2023, 12(7), 1185; https://doi.org/10.3390/antibiotics12071185 - 13 Jul 2023

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Abstract

Acinetobacter baumannii forms air–liquid interface pellicles that boost its ability to withstand desiccation and increase survival under antibiotic pressure. This study aims to delve into the transcriptomic profiles of pellicle cells from clinical strains of carbapenem-resistant A. baumannii (CRAB). The total RNA was extracted from pellicle cells from three pellicle-forming CRAB strains and planktonic cells from three non-pellicle-forming CRAB strains, subject to RNA sequencing using Illumina HiSeq 2500 system. A transcriptomic analysis between pellicle and planktonic cells, along with differential expression genes (DEGs) analysis and enrichment analysis of annotated COGs, GOs, and KEGGs, was performed. Our analysis identified 366 DEGs in pellicle cells: 162 upregulated genes and 204 downregulated genes. The upregulated ABUW_1624 (yiaY) gene and downregulated ABUW_1550 gene indicated potential involvement in fatty acid degradation during pellicle formation. Another upregulated ABUW_2820 (metQ) gene, encoding the D-methionine transporter system, hinted at its contribution to pellicle formation. The upregulation of two-component systems, CusSR and KdpDE, which implies the regulation of copper and potassium ions in a CRAB pellicle formation was also observed. These findings provide valuable insights into the regulation of gene expression during the formation of pellicles in CRAB, and these are potential targets that may aid in the eradication of CRAB infections. Full article

(This article belongs to the Special Issue Antibiotics Resistance in Gram-Negative Bacteria, 2nd Edition)

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16 pages, 1357 KiB

Open AccessArticle

Anaerobic Gram-Negative Bacteria: Role as a Reservoir of Antibiotic Resistance

by Anshul Sood, Pallab Ray and Archana Angrup

Antibiotics 2023, 12(5), 942; https://doi.org/10.3390/antibiotics12050942 - 22 May 2023

Cited by 3 | Viewed by 3540

Abstract

Background: Anaerobic Gram-negative bacteria (AGNB) play a significant role as both pathogens and essential members of the human microbiota. Despite their clinical importance, there remains limited understanding regarding their antimicrobial resistance (AMR) patterns. This knowledge gap poses challenges in effectively managing AGNB-associated infections, as empirical treatment approaches may not adequately address the evolving resistance landscape. To bridge this research gap, we conducted a comprehensive study aimed at exploring the role of human AGNB as a reservoir of AMR. This can provide valuable insights for the prevention and management of anaerobic infections. Methods: We studied the prevalence of AMR and AMR determinants conferring resistance to metronidazole (nimE), imipenem (cfiA), piperacillin–tazobactam (cepA), cefoxitin (cfxA), clindamycin (ermF), chloramphenicol (cat) and mobile genetic elements (MGEs) such as cfiA^IS and IS1186 associated with the cfiA and nim gene expression. These parameters were studied in Bacteroides spp., Fusobacterium spp., Prevotella spp., Veillonella spp., Sutterella spp., and other clinical AGNB. Results: Resistance to metronidazole, clindamycin, imipenem, piperacillin–tazobactam, cefoxitin and chloramphenicol was 29%, 33.5%, 0.5%, 27.5%, 26.5% and 0%, respectively. The presence of resistance genes, viz., nim, ermF, cfiA, cepA, cfxA, was detected in 24%, 33.5%, 10%, 9.5%, 21.5% isolates, respectively. None of the tested isolates showed the presence of a cat gene and MGEs, viz., cfiA^IS and IS1186. The highest resistance to all antimicrobial agents was exhibited by Bacteroides spp. The association between resistant phenotypes and genotypes was complete in clindamycin, as all clindamycin-resistant isolates showed the presence of ermF gene, and none of the susceptible strains harbored this gene; similarly, all isolates were chloramphenicol-susceptible and also lacked the cat gene, whereas the association was low among imipenem and piperacillin–tazobactam. Metronidazole and imipenem resistance was seen to be dependent on insertion sequences for the expression of AMR genes. A constrained co-existence of cepA and cfiA gene in B. fragilis species was seen. Based on the absence and presence of the cfiA gene, we divided B. fragilis into two categories, Division I (72.6%) and Division II (27.3%), respectively. Conclusion: AGNB acts as a reservoir of specific AMR genes, which may pose a threat to other anaerobes due to functional compatibility and acquisition of these genes. Thus, AST-complying standard guidelines must be performed periodically to monitor the local and institutional susceptibility trends, and rational therapeutic strategies must be adopted to direct empirical management. Full article

(This article belongs to the Special Issue Antibiotics Resistance in Gram-Negative Bacteria, 2nd Edition)

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12 pages, 607 KiB

Open AccessReview

From Species to Genes: A New Diagnostic Paradigm

by Sinead Fahy, James A. O’Connor, Roy D. Sleator and Brigid Lucey

Antibiotics 2024, 13(7), 661; https://doi.org/10.3390/antibiotics13070661 - 17 Jul 2024

Cited by 1 | Viewed by 1327

Abstract

Molecular diagnostics has the potential to revolutionise the field of clinical microbiology. Microbial identification and nomenclature have, for too long, been restricted to phenotypic characterisation. However, this species-level view fails to wholly account for genetic heterogeneity, a result of lateral gene transfer, mediated primarily by mobile genetic elements. This genetic promiscuity has helped to drive virulence development, stress adaptation, and antimicrobial resistance in several important bacterial pathogens, complicating their detection and frustrating our ability to control them. We argue that, as clinical microbiologists at the front line, we must embrace the molecular technologies that allow us to focus specifically on the genetic elements that cause disease rather than the bacterial species that express them. This review focuses on the evolution of microbial taxonomy since the introduction of molecular sequencing, the role of mobile genetic elements in antimicrobial resistance, the current and emerging assays in clinical laboratories, and the comparison of phenotypic versus genotypic analyses. In essence, it is time now to refocus from species to genes as part of a new diagnostic paradigm. Full article

(This article belongs to the Special Issue Antibiotics Resistance in Gram-Negative Bacteria, 2nd Edition)

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