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Novel Antimicrobial Strategies to Combat Multidrug-Resistant (MDR) Gram-Negative Bacteria

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

Deadline for manuscript submissions: 31 December 2024 | Viewed by 39786

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Special Issue Editor

Dr. Valerie Carabetta

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Guest Editor

Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, USA
Interests: antibiotic resistance; multidrug resistance; lysine acetylation; KAT; KDAC; histone-like proteins; post-translational modifications; mass spectrometry; proteomics; antimicrobial peptides; biofilm

Special Issue Information

Dear Colleagues,

Infections and mortality caused by Gram-negative bacteria (GNB) are increasing all over the world. Moreover, these types of infections are becoming increasingly more difficult to treat, given the concurrent increase in the prevalence of antibiotic-resistant bacteria. Further compounding this problem is that GNB have a tendency to become resistant to multiple drug classes and are referred to as multidrug-resistant (MDR) GNB, which often leaves physicians with few or no treatment options. GNB possess a plethora of resistance strategies, either intrinsic or acquired, to avoid antibiotic-mediated cell death. Resistance genes and determinants rapidly spread among bacterial populations, which contributes to the rapid emergence MDR strains. Intrinsically, the main weapon of GNB is their cell wall, specifically the outer membrane, which serves as an excellent permeability barrier to drugs and environmental insults. Bacteria can also acquire or evolve resistance to common skin antiseptics and disinfectants, which could contribute to hospital outbreaks of MDR bacteria. Novel strategies to treat and limit the spread of drug-resistant GNB are imperative, and will serve as the primary focus of this Special Issue. This research topic focuses on studies (including original research, methods, perspectives, reviews, and commentaries) that explore and discuss:

New insights into the mechanisms of antibiotic or antiseptic resistance
Determination of novel combinations of drugs to eliminate MDR bacteria
Discovery of novel drug targets for antibiotic development
Evaluation of disinfection practices
Evaluation of the effectiveness of new antibiotics on MDR bacteria
Emergence of new resistance determinants in hospital populations

Dr. Valerie Carabetta
Guest Editor

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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.

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Keywords

Antibiotic resistance
Antiseptic resistance
Multidrug resistant
MDR
Efflux pumps
Mechanisms of resistance
Beta-lactamase
Outer membrane

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Published Papers (11 papers)

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Research

Jump to: Review

31 pages, 2945 KiB

Open AccessArticle

From Shadows to Spotlight: Enhancing Bacterial DNA Detection in Blood Samples through Cutting-Edge Molecular Pre-Amplification

by Martin Reinicke, Sascha Daniel Braun, Celia Diezel, Oliver Lemuth, Ines Engelmann, Theresa Liebe and Ralf Ehricht

Antibiotics 2024, 13(2), 161; https://doi.org/10.3390/antibiotics13020161 - 6 Feb 2024

Viewed by 1577

Abstract

One of the greatest challenges to the use of molecular methods for diagnostic purposes is the detection of target DNA that is present only in low concentrations. One major factor that negatively impacts accuracy, diagnostic sensitivity, and specificity is the sample matrix, which hinders the attainment of the required detection limit due to the presence of residual background DNA. To address this issue, various methods have been developed to enhance sensitivity through targeted pre-amplification of marker sequences. Diagnostic sensitivity to the single molecular level is critical, particularly when identifying bloodstream infections. In cases of clinically manifest sepsis, the concentration of bacteria in the blood may reach as low as one bacterial cell/CFU per mL of blood. Therefore, it is crucial to achieve the highest level of sensitivity for accurate detection. In the present study, we have established a method that fills the analytical gap between low concentrations of molecular markers and the minimum requirements for molecular testing. For this purpose, a sample preparation of whole blood samples with a directly downstream pre-amplification was developed, which amplifies specific species and resistance markers in a multiplex procedure. When applying pre-amplification techniques, the sensitivity of the pathogen detection in whole blood samples was up to 100 times higher than in non-pre-amplified samples. The method was tested with blood samples that were spiked with several Gram-positive and Gram-negative bacterial pathogens. By applying this method to artificial spiked blood samples, it was possible to demonstrate a sensitivity of 1 colony-forming unit (CFU) per millilitre of blood for S. aureus and E. faecium. A detection limit of 28 and 383 CFU per ml of blood was achieved for E. coli and K. pneumoniae, respectively. If the sensitivity is also confirmed for real clinical blood samples from septic patients, the novel technique can be used for pathogen detection without cultivation, which might help to accelerate diagnostics and, thus, to decrease sepsis mortality rates. Full article

(This article belongs to the Special Issue Novel Antimicrobial Strategies to Combat Multidrug-Resistant (MDR) Gram-Negative Bacteria)

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9 pages, 261 KiB

Open AccessArticle

Synergistic Activity of Cefiderocol in Combination with Piperacillin-Tazobactam, Fosfomycin, Ampicillin-Sulbactam, Imipenem-Relebactam and Ceftazidime-Avibactam against Carbapenem-Resistant Gram-Negative Bacteria

by Marta Palombo, Federica Bovo, Stefano Amadesi and Paolo Gaibani

Antibiotics 2023, 12(5), 858; https://doi.org/10.3390/antibiotics12050858 - 5 May 2023

Cited by 10 | Viewed by 2220

Abstract

Limited treatment options are among the main reasons why antimicrobial resistance has become a leading major public health problem. In particular, carbapenem-resistant Enterobacteriales (CRE), Pseudomonas aeruginosa and Acinetobacter baumannii have been included by the World Health Organization (WHO) among the pathogens for which new therapeutic agents are needed. The combination of antibiotics represents an effective strategy to treat multidrug-resistant (MDR) pathogen infections. In this context, the aim of this study is to evaluate the in vitro activity of cefiderocol (CFD) in combination with different antimicrobial molecules against a collection of well-characterized clinical strains, exhibiting different patterns of antimicrobial susceptibility. Clinical strains were genomically characterized using Illumina iSeq100 platform. Synergy analyses were performed by combining CFD with piperacillin-tazobactam (PIP-TAZ), fosfomycin (FOS), ampicillin-sulbactam (AMP-SULB), ceftazidime-avibactam (CAZ-AVI), meropenem-vaborbactam (MER-VAB) and imipenem-relebactam (IMI-REL). Our results demonstrated the synergistic effect of CFD in combination with FOS and CAZ-AVI against CRE and carbapenem-resistant Acinetobacter baumannii (CR-Ab) clinical strains owing CFD-resistant profile, while the CFD and AMP-SULB combination was effective against CR-Pa strain displaying AMP-SULB-resistant profile. Moreover, the combination of CAZ-AVI/SULB showed synergistic activity in CAZ-AVI-resistant CRE strain. In conclusion, although further analyses are needed to confirm these results, our work showed the efficacy of CFD when used for synergistic formulations. Full article

(This article belongs to the Special Issue Novel Antimicrobial Strategies to Combat Multidrug-Resistant (MDR) Gram-Negative Bacteria)

13 pages, 1081 KiB

Open AccessArticle

Evaluating the Efficacy of Eravacycline and Omadacycline against Extensively Drug-Resistant Acinetobacter baumannii Patient Isolates

by Manas S. Deolankar, Rachel A. Carr, Rebecca Fliorent, Sean Roh, Henry Fraimow and Valerie J. Carabetta

Antibiotics 2022, 11(10), 1298; https://doi.org/10.3390/antibiotics11101298 - 23 Sep 2022

Cited by 6 | Viewed by 3657

Abstract

For decades, the spread of multidrug-resistant (MDR) Acinetobacter baumannii has been rampant in critically ill, hospitalized patients. Traditional antibiotic therapies against this pathogen have been failing, leading to rising concerns over management options for patients. Two new antibiotics, eravacycline and omadacycline, were introduced to the market and have shown promising results in the treatment of Gram-negative infections. Since these drugs are newly available, there is limited in vitro data about their effectiveness against MDR A. baumannii or even susceptible strains. Here, we examined the effectiveness of 22 standard-of-care antibiotics, eravacycline, and omadacycline against susceptible and extensively drug-resistant (XDR) A. baumannii patient isolates from Cooper University Hospital. Furthermore, we examined selected combinations of eravacycline or omadacycline with other antibiotics against an XDR strain. We demonstrated that this collection of strains is largely resistant to monotherapies of carbapenems, fluoroquinolones, folate pathway antagonists, cephalosporins, and most tetracyclines. While clinical breakpoint data are not available for eravacycline or omadacycline, based on minimum inhibitory concentrations, eravacycline was highly effective against these strains. The aminoglycoside amikacin alone and in combination with eravacycline or omadacycline yielded the most promising results. Our comprehensive characterization offers direction in the treatment of this deadly infection in hospitalized patients. Full article

(This article belongs to the Special Issue Novel Antimicrobial Strategies to Combat Multidrug-Resistant (MDR) Gram-Negative Bacteria)

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24 pages, 4879 KiB

Open AccessArticle

Guanidinylated Polymyxins as Outer Membrane Permeabilizers Capable of Potentiating Rifampicin, Erythromycin, Ceftazidime and Aztreonam against Gram-Negative Bacteria

by Danzel Marie Ramirez, Danyel Ramirez, Gilbert Arthur, George Zhanel and Frank Schweizer

Antibiotics 2022, 11(10), 1277; https://doi.org/10.3390/antibiotics11101277 - 20 Sep 2022

Cited by 12 | Viewed by 2245

Abstract

Polymyxins are considered a last-line treatment against infections caused by multidrug-resistant (MDR) Gram-negative bacteria. In addition to their use as a potent antibiotic, polymyxins have also been utilized as outer membrane (OM) permeabilizers, capable of augmenting the activity of a partner antibiotic. Several polymyxin derivatives have been developed accordingly, with the objective of mitigating associated nephrotoxicity. The conversion of polymyxins to guanidinylated derivatives, whereby the L-γ-diaminobutyric acid (Dab) amines are substituted with guanidines, are described herein. The resulting guanidinylated colistin and polymyxin B (PMB) exhibited reduced antibacterial activity but preserved OM permeabilizing properties that allowed potentiation of several antibiotic classes. Rifampicin, erythromycin, ceftazidime and aztreonam were particularly potentiated against clinically relevant MDR Gram-negative bacteria. The potentiating effects of guanidinylated polymyxins with ceftazidime or aztreonam were further enhanced by adding the β-lactamase inhibitor avibactam. Full article

(This article belongs to the Special Issue Novel Antimicrobial Strategies to Combat Multidrug-Resistant (MDR) Gram-Negative Bacteria)

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14 pages, 1544 KiB

Open AccessEditor’s ChoiceArticle

In Vitro and In Vivo Antimicrobial Activity of the Novel Peptide OMN6 against Multidrug-Resistant Acinetobacter baumannii

by Janna Michaeli, Shira Mandel, Shelly Maximov, Jonathan Zazoun, Paola Savoia, Nimmi Kothari, Thomas Valmont, Livia Ferrari, Leonard R. Duncan, Stephen Hawser, Moshe Cohen-Kutner and Niv Bachnoff

Antibiotics 2022, 11(9), 1201; https://doi.org/10.3390/antibiotics11091201 - 5 Sep 2022

Cited by 5 | Viewed by 2907

Abstract

The rapid worldwide spread of antimicrobial resistance highlights the significant need for the development of innovative treatments to fight multidrug-resistant bacteria. This study describes the potent antimicrobial activity of the novel peptide OMN6 against a wide array of drug-resistant Acinetobacter baumannii clinical isolates. OMN6 prevented the growth of all tested isolates, regardless of any pre-existing resistance mechanisms. Moreover, in vitro serial-passaging studies demonstrated that no resistance developed against OMN6. Importantly, OMN6 was highly efficacious in treating animal models of lung and blood infections caused by multidrug-resistant A. baumannii. Taken together, these results point to OMN6 as a novel antimicrobial agent with the potential to treat life-threatening infections caused by multidrug-resistant A. baumannii avoiding resistance. Full article

(This article belongs to the Special Issue Novel Antimicrobial Strategies to Combat Multidrug-Resistant (MDR) Gram-Negative Bacteria)

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17 pages, 2135 KiB

Open AccessArticle

Evaluating the Effectiveness of Hospital Antiseptics on Multidrug-Resistant Acinetobacter baumannii: Understanding the Relationship between Microbicide and Antibiotic Resistance

by Melanie Betchen, Holly M. Giovinco, Michael Curry, Jackson Luu, Henry Fraimow, Valerie J. Carabetta and Raquel Nahra

Antibiotics 2022, 11(5), 614; https://doi.org/10.3390/antibiotics11050614 - 3 May 2022

Cited by 12 | Viewed by 3367

Abstract

Acinetobacter baumannii hospital infections are difficult to treat due to the rapid emergence of multidrug-resistant (MDR) strains. In addition, A. baumannii can survive in numerous adverse environments, including in the presence of common hospital antiseptics. We hypothesized that in addition to accumulating drug resistance determinants, MDR A. baumannii strains also accumulate mutations that allow for greater microbicide tolerance when compared to pan-susceptible (PS) strains. To test this hypothesis, we compared the survival of five MDR and five PS patient isolates when exposed to bleach, ethanol, quaternary ammonium compounds, chlorhexidine gluconate, and povidone. We evaluated bacteria in a free-living planktonic state and under biofilm conditions. Each disinfectant eliminated 99.9% of planktonic bacteria, but this was not the case for bacterial biofilms. Next, we characterized strains for the presence of the known microbicide-resistance genes cepA, qacEΔ1, qacE, and qacA. MDR strains did not survive more than PS strains in the presence of microbicides, but microbicide-resistant strains had higher survival rates under some conditions. Interestingly, the PS strains were more likely to possess microbicide-resistance genes. Microbicide resistance remains an important topic in healthcare and may be independent of antimicrobial resistance. Hospitals should consider stricter isolation precautions that take pan-susceptible strains into account. Full article

(This article belongs to the Special Issue Novel Antimicrobial Strategies to Combat Multidrug-Resistant (MDR) Gram-Negative Bacteria)

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Review

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28 pages, 9979 KiB

Open AccessReview

Nanotechnology in the Diagnosis and Treatment of Antibiotic-Resistant Infections

by Petros Ioannou, Stella Baliou and George Samonis

Antibiotics 2024, 13(2), 121; https://doi.org/10.3390/antibiotics13020121 - 25 Jan 2024

Cited by 3 | Viewed by 2657

Abstract

The development of antimicrobial resistance (AMR), along with the relative reduction in the production of new antimicrobials, significantly limits the therapeutic options in infectious diseases. Thus, novel treatments, especially in the current era, where AMR is increasing, are urgently needed. There are several ongoing studies on non-classical therapies for infectious diseases, such as bacteriophages, antimicrobial peptides, and nanotechnology, among others. Nanomaterials involve materials on the nanoscale that could be used in the diagnosis, treatment, and prevention of infectious diseases. This review provides an overview of the applications of nanotechnology in the diagnosis and treatment of infectious diseases from a clinician’s perspective, with a focus on pathogens with AMR. Applications of nanomaterials in diagnosis, by taking advantage of their electrochemical, optic, magnetic, and fluorescent properties, are described. Moreover, the potential of metallic or organic nanoparticles (NPs) in the treatment of infections is also addressed. Finally, the potential use of NPs in the development of safe and efficient vaccines is also reviewed. Further studies are needed to prove the safety and efficacy of NPs that would facilitate their approval by regulatory authorities for clinical use. Full article

(This article belongs to the Special Issue Novel Antimicrobial Strategies to Combat Multidrug-Resistant (MDR) Gram-Negative Bacteria)

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33 pages, 2730 KiB

Open AccessReview

New Antimicrobial Strategies to Treat Multi-Drug Resistant Infections Caused by Gram-Negatives in Cystic Fibrosis

by Viola Camilla Scoffone, Giulia Barbieri, Samuele Irudal, Gabriele Trespidi and Silvia Buroni

Antibiotics 2024, 13(1), 71; https://doi.org/10.3390/antibiotics13010071 - 11 Jan 2024

Cited by 4 | Viewed by 2780

Abstract

People with cystic fibrosis (CF) suffer from recurrent bacterial infections which induce inflammation, lung tissue damage and failure of the respiratory system. Prolonged exposure to combinatorial antibiotic therapies triggers the appearance of multi-drug resistant (MDR) bacteria. The development of alternative antimicrobial strategies may provide a way to mitigate antimicrobial resistance. Here we discuss different alternative approaches to the use of classic antibiotics: anti-virulence and anti-biofilm compounds which exert a low selective pressure; phage therapies that represent an alternative strategy with a high therapeutic potential; new methods helping antibiotics activity such as adjuvants; and antimicrobial peptides and nanoparticle formulations. Their mechanisms and in vitro and in vivo efficacy are described, in order to figure out a complete landscape of new alternative approaches to fight MDR Gram-negative CF pathogens. Full article

(This article belongs to the Special Issue Novel Antimicrobial Strategies to Combat Multidrug-Resistant (MDR) Gram-Negative Bacteria)

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24 pages, 1395 KiB

Open AccessReview

Bacteriophages in Infectious Diseases and Beyond—A Narrative Review

by Petros Ioannou, Stella Baliou and George Samonis

Antibiotics 2023, 12(6), 1012; https://doi.org/10.3390/antibiotics12061012 - 5 Jun 2023

Cited by 15 | Viewed by 5380

Abstract

The discovery of antibiotics has revolutionized medicine and has changed medical practice, enabling successful fighting of infection. However, quickly after the start of the antibiotic era, therapeutics for infectious diseases started having limitations due to the development of antimicrobial resistance. Since the antibiotic pipeline has largely slowed down, with few new compounds being produced in the last decades and with most of them belonging to already-existing classes, the discovery of new ways to treat pathogens that are resistant to antibiotics is becoming an urgent need. To that end, bacteriophages (phages), which are already used in some countries in agriculture, aquaculture, food safety, and wastewater plant treatments, could be also used in clinical practice against bacterial pathogens. Their discovery one century ago was followed by some clinical studies that showed optimistic results that were limited, however, by some notable obstacles. However, the rise of antibiotics during the next decades left phage research in an inactive status. In the last decades, new studies on phages have shown encouraging results in animals. Hence, further studies in humans are needed to confirm their potential for effective and safe treatment in cases where there are few or no other viable therapeutic options. This study reviews the biology and applications of phages for medical and non-medical uses in a narrative manner. Full article

(This article belongs to the Special Issue Novel Antimicrobial Strategies to Combat Multidrug-Resistant (MDR) Gram-Negative Bacteria)

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13 pages, 1222 KiB

Open AccessReview

Extracellular Vesicles of Pseudomonas: Friends and Foes

by Tania Henriquez and Chiara Falciani

Antibiotics 2023, 12(4), 703; https://doi.org/10.3390/antibiotics12040703 - 4 Apr 2023

Cited by 6 | Viewed by 2039

Abstract

Extracellular vesicles (Evs) are small spherical vesicles capable of transporting molecules (such as proteins, nucleic acids and lipids) from one cell to another. They have been implicated in processes such as cell-to-cell communication, pathogenicity, biofilm formation and metabolism. In parallel, Evs have been proposed as interesting biotechnological tools. In recent years, antibiotic resistance has become a major problem for human health worldwide. A pathogen singled out as among the most lethal antibiotic-resistant organisms is Pseudomonas aeruginosa, an important Gram-negative bacterium that has been extensively studied for the production and characterization of Evs. Here, we describe the advances made in the last decade regarding understanding of the role of Evs in the pathogenicity of Pseudomonas. We also examine the potential of Evs for the development of new treatment strategies. Full article

(This article belongs to the Special Issue Novel Antimicrobial Strategies to Combat Multidrug-Resistant (MDR) Gram-Negative Bacteria)

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19 pages, 3531 KiB

Open AccessReview

Antimicrobial Peptides: From Design to Clinical Application

by Chunye Zhang and Ming Yang

Antibiotics 2022, 11(3), 349; https://doi.org/10.3390/antibiotics11030349 - 6 Mar 2022

Cited by 67 | Viewed by 8884

Abstract

Infection of multidrug-resistant (MDR) bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), carbapenem-resistant Enterobacteriaceae (CRE), and extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli, brings public health issues and causes economic burden. Pathogenic bacteria develop several methods to resist antibiotic killing or inhibition, such as mutation of antibiotic function sites, activation of drug efflux pumps, and enzyme-mediated drug degradation. Antibiotic resistance components can be transferred between bacteria by mobile genetic elements including plasmids, transposons, and integrons, as well as bacteriophages. The development of antibiotic resistance limits the treatment options for bacterial infection, especially for MDR bacteria. Therefore, novel or alternative antibacterial agents are urgently needed. Antimicrobial peptides (AMPs) display multiple killing mechanisms against bacterial infections, including directly bactericidal activity and immunomodulatory function, as potential alternatives to antibiotics. In this review, the development of antibiotic resistance, the killing mechanisms of AMPs, and especially, the design, optimization, and delivery of AMPs are reviewed. Strategies such as structural change, amino acid substitution, conjugation with cell-penetration peptide, terminal acetylation and amidation, and encapsulation with nanoparticles will improve the antimicrobial efficacy, reduce toxicity, and accomplish local delivery of AMPs. In addition, clinical trials in AMP studies or applications of AMPs within the last five years were summarized. Overall, AMPs display diverse mechanisms of action against infection of pathogenic bacteria, and future research studies and clinical investigations will accelerate AMP application. Full article

(This article belongs to the Special Issue Novel Antimicrobial Strategies to Combat Multidrug-Resistant (MDR) Gram-Negative Bacteria)

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