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Multidrug Resistance in Bacteria and New Therapeutic Options

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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (20 May 2024) | Viewed by 29945

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Dr. Gordana Maravić Vlahoviček

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Guest Editor

Department of Biochemistry and Molecular Biology, Faculty of Pharmacy and Biochemistry, University of Zagreb, Ante Kovačića 1, 10000 Zagreb, Croatia
Interests: ribosomal antibiotics; mechanisms of resistance; quorum sensing and biofilm

Dr. Branka Bedenić

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Guest Editor

School of Medicine, University of Zagreb, Šalata ul. 2, 10000 Zagreb, Croatia
Interests: beta-lactamases; carbapenemases; extended-spectrum beta-lactamases; resistance

Special Issue Information

Dear Colleagues,

Antimicrobial resistance presents a critical threat to public health and a great challenge to clinicians treating patients in intensive care units. Carbapenem resistance is increasing in Enterobacterales (CRE), Pseudomonas aeruginosa (CRPA) and Acinetobacter baumannii (CRAB). The rate of carbapenem resistance has increased to over 10% in Enterobacterales and over 90% in A. baumannii in geographic regions such as East Europe and the Mediterranean area. Colistin, which is neurotoxic and nephrotoxic, is often the last-resort antibiotic. However, colistin-resistant isolates have recently emerged among Enterobacterales, A. baumannii and occasionally, although rarely, P. aeruginosa. Clinicians often do not have any other therapeutic option, and have to rely on antibiotic combinations in order to treat the patient. In the last few years, new antibiotics have been licenced for the treatment of infections due to CRE, CRAB and CRPA, including ceftolozan/tazobactam (CTA) ceftazidime/avibactam (CZA), imipenem/cilastatin/relebactam (IMR) and cefiderocol, as well as eravacycline, which is efficient against MRSA and VRE. The majority of these antibiotics exert good activity against KPC- and OXA-48-producing Enterobacterales and CRPA, but with the exception of cefiderocol, do not exhibit any activity against metalo-beta-lactamase-producing organisms or CRAB. Thus, the scope of this Special Issue is mostly focused on the in vitro and in vivo activity of the novel compounds for the treatment of infections associated with CRE, CRPA and CRAB.

Topics of interest include, but are not limited to:

In vitro activity of the novel compounds (CZA, CTA, IMR, cefiderocol, eravacycline, including compounds currently in development) against multidrug or extensively drug Gram-negative and Gram-positive pathogens in human and veterinary medicine;
Mechanisms of bacterial resistance to novel drugs and molecular epidemiology of resistant isolates in humans, animals and the environment;
Clinical trials with new antibiotics.

Dr. Gordana Maravić Vlahoviček
Dr. Branka Bedenić
Guest Editors

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Keywords

multidrug-resistant bacteria (MDR)
carbapenem-resistant enterobacterales (CREs)
carbapenem-resistant Pseudomonas aeruginosa (CRPA)
carbapenem-resistant Acinetobacter baumannii (CRAB)
ceftolozan/tazobactam (CTA) ceftazidime/avibactam (CZA)
imipenem/cilastatin/relebactam (IMR)
cefiderocol

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Published Papers (10 papers)

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Research

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13 pages, 1595 KiB

Open AccessArticle

In Vitro Antibiofilm Activity of Fosfomycin Alone and in Combination with Other Antibiotics against Multidrug-Resistant and Extensively Drug-Resistant Pseudomonas aeruginosa

by Mia Slade-Vitković, Ivanka Batarilo, Luka Bielen, Gordana Maravić-Vlahoviček and Branka Bedenić

Pharmaceuticals 2024, 17(6), 769; https://doi.org/10.3390/ph17060769 - 12 Jun 2024

Cited by 1 | Viewed by 1205

Abstract

Background: Due to its rapid resistance development and ability to form biofilms, treatment of Pseudomonas aeruginosa infections is becoming more complicated by the day. Drug combinations may help reduce both resistance and biofilm formation. Methods: Using the microtiter plate assay, we investigated the in vitro inhibition of biofilm formation and the disruption of preformed biofilms in multidrug-resistant and extensively drug-resistant clinical isolates of P. aeruginosa in the presence of peak plasma levels of eight antipseudomonal antibiotics alone and in combination with fosfomycin: ceftazidime, piperacillin/tazobactam, cefepime, imipenem, gentamicin, amikacin, ciprofloxacin and colistin. Results: Combination therapy was significantly superior to monotherapy in its inhibition of biofilm formation. The highest inhibition rates were observed for combinations with colistin, cefepime and ceftazidime. Conclusion: Our results support fosfomycin combination therapy as an enhanced prophylactic option. Moreover, combinations with β-lactam antibiotics and colistin demonstrated a more potent inhibition effect on biofilm formation than protein synthesis inhibitors. Full article

(This article belongs to the Special Issue Multidrug Resistance in Bacteria and New Therapeutic Options)

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24 pages, 5840 KiB

Open AccessArticle

Discovery of Bacterial Key Genes from 16S rRNA-Seq Profiles That Are Associated with the Complications of SARS-CoV-2 Infections and Provide Therapeutic Indications

by Md. Kaderi Kibria, Md. Ahad Ali, Muhammad Yaseen, Imran Ahmad Khan, Mashooq Ahmad Bhat, Md. Ariful Islam, Rashidul Alam Mahumud and Md. Nurul Haque Mollah

Pharmaceuticals 2024, 17(4), 432; https://doi.org/10.3390/ph17040432 - 28 Mar 2024

Viewed by 1933

Abstract

SARS-CoV-2 infections, commonly referred to as COVID-19, remain a critical risk to both human life and global economies. Particularly, COVID-19 patients with weak immunity may suffer from different complications due to the bacterial co-infections/super-infections/secondary infections. Therefore, different variants of alternative antibacterial therapeutic agents are required to inhibit those infection-causing drug-resistant pathogenic bacteria. This study attempted to explore these bacterial pathogens and their inhibitors by using integrated statistical and bioinformatics approaches. By analyzing bacterial 16S rRNA sequence profiles, at first, we detected five bacterial genera and taxa (Bacteroides, Parabacteroides, Prevotella Clostridium, Atopobium, and Peptostreptococcus) based on differentially abundant bacteria between SARS-CoV-2 infection and control samples that are significantly enriched in 23 metabolic pathways. A total of 183 bacterial genes were found in the enriched pathways. Then, the top-ranked 10 bacterial genes (accB, ftsB, glyQ, hldD, lpxC, lptD, mlaA, ppsA, ppc, and tamB) were selected as the pathogenic bacterial key genes (bKGs) by their protein–protein interaction (PPI) network analysis. Then, we detected bKG-guided top-ranked eight drug molecules (Bemcentinib, Ledipasvir, Velpatasvir, Tirilazad, Acetyldigitoxin, Entreatinib, Digitoxin, and Elbasvir) by molecular docking. Finally, the binding stability of the top-ranked three drug molecules (Bemcentinib, Ledipasvir, and Velpatasvir) against three receptors (hldD, mlaA, and lptD) was investigated by computing their binding free energies with molecular dynamic (MD) simulation-based MM-PBSA techniques, respectively, and was found to be stable. Therefore, the findings of this study could be useful resources for developing a proper treatment plan against bacterial co-/super-/secondary-infection in SARS-CoV-2 infections. Full article

(This article belongs to the Special Issue Multidrug Resistance in Bacteria and New Therapeutic Options)

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12 pages, 780 KiB

Open AccessArticle

Antimicrobial Activity of Ceragenins against Vancomycin-Susceptible and -Resistant Enterococcus spp.

by Mayram Hacioglu, Fatima Nur Yilmaz, Ozlem Oyardi, Cagla Bozkurt Guzel, Nese Inan, Paul B. Savage and Sibel Dosler

Pharmaceuticals 2023, 16(12), 1643; https://doi.org/10.3390/ph16121643 - 23 Nov 2023

Cited by 1 | Viewed by 1283

Abstract

Ceragenins (CSAs) are a new class of antimicrobial agents designed to mimic the activities of endogenous antimicrobial peptides. In this study, the antibacterial activities of various ceragenins (CSA-13, CSA-44, CSA-90, CSA-131, CSA-138, CSA-142, and CSA-192), linezolid, and daptomycin were assessed against 50 non-repeated Enterococcus spp. (17 of them vancomycin-resistant Enterococcus-VRE) isolated from various clinical specimens. Among the ceragenins evaluated, the MIC₅₀ and MIC₉₀ values of CSA-44 and CSA-192 were the lowest (2 and 4 μg/mL, respectively), and further studies were continued with these two ceragenins. Potential interactions between CSA-44 or CSA-192 and linezolid were tested and synergistic interactions were seen with the CSA-192-linezolid combination against three Enterococcus spp., one of them VRE. The effects of CSA-44 and CSA-192 on the MIC values of vancomycin were also investigated, and the largest MIC change was seen in the vancomycin-CSA-192 combination. The in vivo effects of CSA-44 and CSA-192 were evaluated in a Caenorhabditis elegans model system. Compared to no treatment, increased survival was observed with C. elegans when treated with ceragenins. In conclusion, CSA-44 and CSA-192 appear to be good candidates (alone or in combination) for the treatment of enterococcal infections, including those from VRE. Full article

(This article belongs to the Special Issue Multidrug Resistance in Bacteria and New Therapeutic Options)

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16 pages, 5468 KiB

Open AccessArticle

Impact of Solidago virgaurea Extract on Biofilm Formation for ESBL-Pseudomonas aeruginosa: An In Vitro Model Study

by Ali Hazim Abdulkareem, Anmar Kamil Alalwani, Mohammed Mukhles Ahmed, Safaa Abed Latef Al-Meani, Mohammed Salih Al-Janaby, Al-Moghira Khairi Al-Qaysi, Ali Ibrahim Edan and Hasan Falah Lahij

Pharmaceuticals 2023, 16(10), 1383; https://doi.org/10.3390/ph16101383 - 29 Sep 2023

Cited by 4 | Viewed by 1597

Abstract

The increasing disparity between antimicrobial resistance (AMR) and the development of new antimicrobials continues to pose a significant global health concern. However, plant extracts have shown promise in combating this issue either through their inherent antimicrobial activity or by serving as potential reservoirs [...] Read more.

β

-lactamases (ESBLs). However, there is limited research available on the antibacterial properties of goldenrod extract. Thus, the objective of this study was to investigate the impact of S. virgaurea (SV) extract on the viability and ability to form biofilms of ESBL-Pseudomonas aeruginosa (P. aeruginosa). A cross-sectional study was conducted from August 2022 to March 2023. The broth microdilution method was employed to determine the minimum inhibitory concentration (MIC) of the (SV) extract. Subsequently, the minimum bactericidal concentration (MBC) was determined based on the MIC values obtained. The antibiotic susceptibility of bacteria was evaluated using the Kirby disk diffusion assay and an Antimicrobial Susceptibility Testing (AST) card in conjunction with the Vitek-2 compact system. Biofilm formation was evaluated using Congo red and a 96-well Elisa plate, while the presence of extended-spectrum β-lactamases (ESBLs) was estimated by measuring the reduction of nitrocefin at a wavelength of 390 nm. In addition, treatment of biofilm and ESBL activity with SV extract using 96-well Elisa plate and nitrocefin hydrolyzing, respectively. The resistance rates of P. aeruginosa isolates to the tested antibiotics were as follows: Levofloxacin 33%, Ciprofloxacin 40%, Amikacin 49%, Meropenem 50%, Cefepime 70%, Ceftazidime 75%, Cefotaxime 85%, Piperacillin-Tazobactam 90%, Amoxiclav 97%, Ampicillin 99%, Ceftriaxone 100%. The prevalence of MDR-P. aeruginosa, XDR-P. aeruginosa, PDR-P. aeruginosa and non-MDR-PA were 40% (n = 40), 7% (n = 7), 3% (n = 3) and 50% (n = 50), respectively. From the GC–MS results, it was observed that the presence of Octadecane, Clioquinol, Glycerol tricaprylate, hexadecanoic acid, cis-13-octadecenoic acid, oleic acid and Propanamide were the major components in the Solidago extract. In the determination of plant crude extracts, the values ranged between 0.25 and 64 mg/mL against bacteria. The resulting activity of the extract showed a significant statistical relationship at a p-value ≤ 0.01 against ESBL production and biofilm formation in P. aeruginosa. The S. virgaurea extract exhibited effectiveness in inhibiting biofilm formation and combating P. aeruginosa strains that produce extended-spectrum β-lactamases (ESBLs). Full article

(This article belongs to the Special Issue Multidrug Resistance in Bacteria and New Therapeutic Options)

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25 pages, 12293 KiB

Open AccessArticle

Comprehensive Characterization of a Streptococcus agalactiae Phage Isolated from a Tilapia Farm in Selangor, Malaysia, and Its Potential for Phage Therapy

by Megat Hamzah Megat Mazhar Khair, An Nie Tee, Nurul Fazlin Wahab, Siti Sarah Othman, Yong Meng Goh, Mas Jaffri Masarudin, Chou Min Chong, Lionel Lian Aun In, Han Ming Gan and Adelene Ai-Lian Song

Pharmaceuticals 2023, 16(5), 698; https://doi.org/10.3390/ph16050698 - 5 May 2023

Cited by 1 | Viewed by 3215

Abstract

The Streptococcus agalactiae outbreak in tilapia has caused huge losses in the aquaculture industry worldwide. In Malaysia, several studies have reported the isolation of S. agalactiae, but no study has reported the isolation of S. agalactiae phages from tilapia or from the culture pond. Here, the isolation of the S. agalactiae phage from infected tilapia is reported and it is named as vB_Sags-UPM1. Transmission electron micrograph (TEM) revealed that this phage showed characteristics of a Siphoviridae and it was able to kill two local S. agalactiae isolates, which were S. agalactiae smyh01 and smyh02. Whole genome sequencing (WGS) of the phage DNA showed that it contained 42,999 base pairs with 36.80% GC content. Bioinformatics analysis predicted that this phage shared an identity with the S. agalactiae S73 chromosome as well as several other strains of S. agalactiae, presumably due to prophages carried by these hosts, and it encodes integrase, which suggests that it was a temperate phage. The endolysin of vB_Sags-UPM1 termed Lys60 showed killing activity on both S. agalactiae strains with varying efficacy. The discovery of the S. agalactiae temperate phage and its antimicrobial genes could open a new window for the development of antimicrobials to treat S. agalactiae infection. Full article

(This article belongs to the Special Issue Multidrug Resistance in Bacteria and New Therapeutic Options)

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12 pages, 1958 KiB

Open AccessArticle

Penetration of Triphenylphosphonium Derivatives through the Cell Envelope of Bacteria of Mycobacteriales Order

by Pavel A. Nazarov, Konstantin B. Majorov, Alexander S. Apt and Maxim V. Skulachev

Pharmaceuticals 2023, 16(5), 688; https://doi.org/10.3390/ph16050688 - 2 May 2023

Cited by 4 | Viewed by 1963

Abstract

The penetration of substances through the bacterial cell envelope is a complex and underinvestigated process. Mitochondria-targeted antioxidant and antibiotic SkQ1 (10-(plastoquinonyl)decyltriphenylphosphonium) is an excellent model for studying the penetration of substances through the bacterial cell envelope. SkQ1 resistance in Gram-negative bacteria has been found to be dependent on the presence of the AcrAB-TolC pump, while Gram-positive bacteria do not have this pump but, instead, have a mycolic acid-containing cell wall that is a tough barrier against many antibiotics. Here, we report the bactericidal action of SkQ1 and dodecyl triphenylphospho-nium (C₁₂TPP) against Rhodococcus fascians and Mycobacterium tuberculosis, pathogens of plants and humans. The mechanism of the bactericidal action is based on the penetration of SkQ1 and C₁₂TPP through the cell envelope and the disruption of the bioenergetics of bacteria. One, but probably not the only such mechanism is a decrease in membrane potential, which is important for the implementation of many cellular processes. Thus, neither the presence of MDR pumps, nor the presence of porins, prevents the penetration of SkQ1 and C₁₂TPP through the complex cell envelope of R. fascians and M. tuberculosis. Full article

(This article belongs to the Special Issue Multidrug Resistance in Bacteria and New Therapeutic Options)

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Review

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19 pages, 686 KiB

Open AccessReview

Bacteriophages and Their Host Range in Multidrug-Resistant Bacterial Disease Treatment

by Ka Mun Chung, Xiew Leng Liau and Swee Seong Tang

Pharmaceuticals 2023, 16(10), 1467; https://doi.org/10.3390/ph16101467 - 16 Oct 2023

Cited by 10 | Viewed by 3109

Abstract

The rapid emergence of multidrug-resistant (MDR) bacteria in recent times has prompted the search for new and more potent antibiotics. Bacteriophages (commonly known as phages) are viruses that target and infect their bacterial hosts. As such, they are also a potential alternative to antibiotics. These phages can be broadly categorized into monovalent (with a narrow host range spectrum and specific to a single bacterial genus) and polyvalent (with a broad host range and specific to more than two genera). However, there is still much ambiguity in the use of these terms, with researchers often describing their phages differently. There is considerable research on the use of both narrow- and broad-host range phages in the treatment of infections and diseases caused by MDR bacteria, including tuberculosis, cystic fibrosis, and carbapenem-resistant Enterobacterales (CRE) infectious diseases. From this, it is clear that the host range of these phages plays a vital role in determining the effectiveness of any phage therapy, and this factor is usually analyzed based on the advantages and limitations of different host ranges. There have also been efforts to expand phage host ranges via phage cocktail development, phage engineering and combination therapies, in line with current technological advancements. This literature review aims to provide a more in-depth understanding of the role of phage host ranges in the effectiveness of treating MDR-bacterial diseases, by exploring the following: phage biology, the importance of phages in MDR bacteria diseases treatment, the importance of phage host range and its advantages and limitations, current findings and recent developments, and finally, possible future directions for wide host range phages. Full article

(This article belongs to the Special Issue Multidrug Resistance in Bacteria and New Therapeutic Options)

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21 pages, 795 KiB

Open AccessReview

The Safety of Bacteriophages in Treatment of Diseases Caused by Multidrug-Resistant Bacteria

by Ka Mun Chung, Sue C. Nang and Swee Seong Tang

Pharmaceuticals 2023, 16(10), 1347; https://doi.org/10.3390/ph16101347 - 24 Sep 2023

Cited by 13 | Viewed by 6059

Abstract

Given the urgency due to the rapid emergence of multidrug-resistant (MDR) bacteria, bacteriophages (phages), which are viruses that specifically target and kill bacteria, are rising as a potential alternative to antibiotics. In recent years, researchers have begun to elucidate the safety aspects of phage therapy with the aim of ensuring safe and effective clinical applications. While phage therapy has generally been demonstrated to be safe and tolerable among animals and humans, the current research on phage safety monitoring lacks sufficient and consistent data. This emphasizes the critical need for a standardized phage safety assessment to ensure a more reliable evaluation of its safety profile. Therefore, this review aims to bridge the knowledge gap concerning phage safety for treating MDR bacterial infections by covering various aspects involving phage applications, including phage preparation, administration, and the implications for human health and the environment. Full article

(This article belongs to the Special Issue Multidrug Resistance in Bacteria and New Therapeutic Options)

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32 pages, 958 KiB

Open AccessReview

CRISPR-Based Gene Editing in Acinetobacter baumannii to Combat Antimicrobial Resistance

by Muhammad Junaid, Krit Thirapanmethee, Piyatip Khuntayaporn and Mullika Traidej Chomnawang

Pharmaceuticals 2023, 16(7), 920; https://doi.org/10.3390/ph16070920 - 23 Jun 2023

Cited by 6 | Viewed by 4646

Abstract

Antimicrobial resistance (AMR) poses a significant threat to the health, social, environment, and economic sectors on a global scale and requires serious attention to addressing this issue. Acinetobacter baumannii was given top priority among infectious bacteria because of its extensive resistance to nearly all antibiotic classes and treatment options. Carbapenem-resistant A. baumannii is classified as one of the critical-priority pathogens on the World Health Organization (WHO) priority list of antibiotic-resistant bacteria for effective drug development. Although available genetic manipulation approaches are successful in A. baumannii laboratory strains, they are limited when employed on newly acquired clinical strains since such strains have higher levels of AMR than those used to select them for genetic manipulation. Recently, the CRISPR-Cas (Clustered regularly interspaced short palindromic repeats/CRISPR-associated protein) system has emerged as one of the most effective, efficient, and precise methods of genome editing and offers target-specific gene editing of AMR genes in a specific bacterial strain. CRISPR-based genome editing has been successfully applied in various bacterial strains to combat AMR; however, this strategy has not yet been extensively explored in A. baumannii. This review provides detailed insight into the progress, current scenario, and future potential of CRISPR-Cas usage for AMR-related gene manipulation in A. baumannii. Full article

(This article belongs to the Special Issue Multidrug Resistance in Bacteria and New Therapeutic Options)

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11 pages, 785 KiB

Open AccessReview

Mechanisms of Linezolid Resistance in Mycobacteria

by Wei Chong Gan, Hien Fuh Ng and Yun Fong Ngeow

Pharmaceuticals 2023, 16(6), 784; https://doi.org/10.3390/ph16060784 - 24 May 2023

Cited by 8 | Viewed by 3774

Abstract

Mycobacteria form some of the most notorious and difficult-to-treat bacterial pathogens. As a group, they are intrinsically resistant to many commonly used antibiotics, such as tetracyclines and beta-lactams. In addition to intrinsic resistances, acquired multidrug resistance has also been observed and documented in Mycobacterium tuberculosis (MTB), Mycobacterium leprae and non-tuberculous mycobacteria (NTM). To combat multidrug resistant infections by these pathogens, innovative antimicrobials and treatment regimens are required. In this regard, linezolid, an oxazolidinone introduced for clinical use just two decades ago, was added to the therapeutic armamentarium for drug-resistant mycobacteria. It exhibits antibacterial activity by binding to the 50S ribosomal subunit and inhibiting protein synthesis. Unfortunately, linezolid resistance has now been documented in MTB and NTM, in many parts of the world. Most linezolid-resistant mycobacterial strains show mutations in the ribosome or related genes, such as in the rplC, rrl and tsnR genes. Non-ribosomal mechanisms appear to be rare. One such mechanism was associated with a mutation in fadD32, which encodes a protein that plays an important role in mycolic acid synthesis. Mycobacterial efflux proteins have also been implicated in linezolid resistance. This review summarises current knowledge of genetic determinants of linezolid resistance in mycobacteria, with the aim of contributing information that could facilitate the discovery of new therapeutic approaches to overcome, delay or avoid further developments of drug resistance among these important pathogens. Full article

(This article belongs to the Special Issue Multidrug Resistance in Bacteria and New Therapeutic Options)

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