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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Microbiology".

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 31806

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Special Issue Editor

Dr. Cidália Pina-Vaz

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Guest Editor

1. Department of Microbiology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
2. CINTESIS, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
Interests: antimicrobial susceptibility assays; microbial mechanisms of resistance; flow cytometry and microbiology; rapid antimicrobial susceptibility assays
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Special Issue Information

Dear Colleagues,

Health care has been a hot topic recently. Before this COVID-19 pandemic, antimicrobial resistance was already a major global concern. During it and surely after it, this topic will continue to be a cause of global concern and an urgent topic to work on. Infectious disease treatment requires disruptive strategies, including new drugs, knowledge about mechanisms of resistance, and faster diagnostic tests. New drugs are necessary, entailing the development of new molecules and the search for alternative microbe targets. Molecular knowledge of the underlined mechanisms of resistance would help to eventually revert resistance and recover some old molecules. Additionally but no less important is the development of rapid solutions from microbiology labs in order to guide antimicrobial therapy, avoiding broad-spectrum empiric treatment. To help antimicrobial stewardship, the development of antimicrobial dosing for some drugs and in special patients is also a required.

Prof. Dr. Cidália Pina-Vaz
Guest Editor

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Keywords

antimicrobial resistance
mechanisms of antimicrobial resistance
rapid antimicrobial susceptible assays
antimicrobial dosing
molecular assays

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Published Papers (9 papers)

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Research

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19 pages, 3911 KiB

Open AccessArticle

Clinical Breakpoint of Apramycin to Swine Salmonella and Its Effect on Ileum Flora

by Xinyu Dai, Yufeng Gu, Jinli Guo, Lingli Huang, Guyue Cheng, Dapeng Peng and Haihong Hao

Int. J. Mol. Sci. 2022, 23(3), 1424; https://doi.org/10.3390/ijms23031424 - 26 Jan 2022

Cited by 2 | Viewed by 3195

Abstract

The purpose of this study was to establish the clinical breakpoint (CBP) of apramycin (APR) against Salmonella in swine and evaluate its effect on intestinal microbiota. The CBP was established based on three cutoff values of wild-type cutoff value (CO_WT), pharmacokinetic-pharmadynamic (PK/PD) cutoff value (CO_PD) and clinical cutoff value (CO_CL). The effect of the optimized dose regimen based on ex vivo PK/PD study. The evolution of the ileum flora was determined by the 16rRNA gene sequencing and bioinformatics. This study firstly established the CO_WT, CO_PD in ileum, and CO_CL of APR against swine Salmonella, the value of these cutoffs were 32 µg/mL, 32 µg/mL and 8 µg/mL, respectively. According to the guiding principle of the Clinical Laboratory Standards Institute (CLSI), the final CBP in ileum was 32 µg/mL. Our results revealed the main evolution route in the composition of ileum microbiota of diarrheic piglets treated by APR. The change of the abundances of Bacteroidetes and Euryarchaeota was the most obvious during the evolution process. Methanobrevibacter, Prevotella, S24-7 and Ruminococcaceae were obtained as the highest abundance genus. The abundance of Methanobrevibacter increased significantly when APR treatment carried and decreased in cure and withdrawal period groups. The abundance of Prevotella in the tested groups was significantly lower than that in the healthy group. A decreased of abundance in S24-7 was observed after Salmonella infection and increased slightly after cure. Ruminococcaceae increased significantly after Salmonella infection and decreased significantly after APR treatment. In addition, the genera of Methanobrevibacter and Prevotella were defined as the key node. Valine, leucine and isoleucine biosynthesis, D-Glutamine and D-glutamate metabolism, D-Alanine metabolism, Peptidoglycan and amino acids biosynthesis were the top five Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways in the ileum microbiota of piglets during the Salmonella infection and APR treatment process. Our study extended the understanding of dynamic shift of gut microbes during diarrheic piglets treated by APR. Full article

(This article belongs to the Special Issue Antimicrobial Resistance-New Insights)

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15 pages, 18285 KiB

Open AccessArticle

Rapid, Label-Free Prediction of Antibiotic Resistance in Salmonella typhimurium by Surface-Enhanced Raman Spectroscopy

by Ping Zhang, Xi-Hao Wu, Lan Su, Hui-Qin Wang, Tai-Feng Lin, Ya-Ping Fang, Hui-Min Zhao, Wen-Jing Lu, Meng-Jia Liu, Wen-Bo Liu and Da-Wei Zheng

Int. J. Mol. Sci. 2022, 23(3), 1356; https://doi.org/10.3390/ijms23031356 - 25 Jan 2022

Cited by 11 | Viewed by 2926

Abstract

The rapid identification of bacterial antibiotic susceptibility is pivotal to the rational administration of antibacterial drugs. In this study, cefotaxime (CTX)-derived resistance in Salmonella typhimurium (abbr. CTX^r-S. typhimurium) during 3 months of exposure was rapidly recorded using a portable Raman spectrometer. The molecular changes that occurred in the drug-resistant strains were sensitively monitored in whole cells by label-free surface-enhanced Raman scattering (SERS). Various degrees of resistant strains could be accurately discriminated by applying multivariate statistical analyses to bacterial SERS profiles. Minimum inhibitory concentration (MIC) values showed a positive linear correlation with the relative Raman intensities of I₉₉₀/I₁₃₄₈, and the R² reached 0.9962. The SERS results were consistent with the data obtained by MIC assays, mutant prevention concentration (MPC) determinations, and Kirby-Bauer antibiotic susceptibility tests (K-B tests). This preliminary proof-of-concept study indicates the high potential of the SERS method to supplement the time-consuming conventional method and help alleviate the challenges of antibiotic resistance in clinical therapy. Full article

(This article belongs to the Special Issue Antimicrobial Resistance-New Insights)

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20 pages, 2172 KiB

Open AccessArticle

Fosfomycin Resistance Evolutionary Pathways of Stenotrophomonas maltophilia in Different Growing Conditions

by Teresa Gil-Gil and José L. Martínez

Int. J. Mol. Sci. 2022, 23(3), 1132; https://doi.org/10.3390/ijms23031132 - 20 Jan 2022

Cited by 6 | Viewed by 2075

Abstract

The rise of multidrug-resistant Gram-negative pathogens and the lack of novel antibiotics to address this problem has led to the rescue of old antibiotics without a relevant use, such as fosfomycin. Stenotrophomonas maltophilia is a Gram-negative, non-fermenter opportunistic pathogen that presents a characteristic low susceptibility to several antibiotics of common use. Previous work has shown that while the so-far described mechanisms of fosfomycin resistance in most bacteria consist of the inactivation of the target or the transporters of this antibiotic, as well as the production of antibiotic-inactivating enzymes, these mechanisms are not selected in S. maltophilia fosfomycin-resistant mutants. In this microorganism, fosfomycin resistance is caused by the inactivation of enzymes belonging to its central carbon metabolism, hence linking metabolism with antibiotic resistance. Consequently, it is relevant to determine how different growing conditions, including urine and synthetic sputum medium that resemble infection, could impact the evolutionary pathways towards fosfomycin resistance in S. maltophilia. Our results show that S. maltophilia is able to acquire high-level fosfomycin resistance under all tested conditions. However, although some of the genetic changes leading to resistance are common, there are specific mutations that are selected under each of the tested conditions. These results indicate that the pathways of S. maltophilia evolution can vary depending on the infection point and provide information for understanding in more detail the routes of fosfomycin resistance evolution in S. maltophilia. Full article

(This article belongs to the Special Issue Antimicrobial Resistance-New Insights)

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27 pages, 4007 KiB

Open AccessArticle

The Antibiotic Fosfomycin Mimics the Effects of the Intermediate Metabolites Phosphoenolpyruvate and Glyceraldehyde-3-Phosphate on the Stenotrophomonas maltophilia Transcriptome

by Teresa Gil-Gil, Luz Edith Ochoa-Sánchez and José Luis Martínez

Int. J. Mol. Sci. 2022, 23(1), 159; https://doi.org/10.3390/ijms23010159 - 23 Dec 2021

Cited by 6 | Viewed by 3342

Abstract

Stenotrophomonas maltophilia is an opportunistic pathogen with an environmental origin, which presents a characteristically low susceptibility to antibiotics and is capable of acquiring increased levels of resistance to antimicrobials. Among these, fosfomycin resistance seems particularly intriguing; resistance to this antibiotic is generally due to the activity of fosfomycin-inactivating enzymes, or to defects in the expression or the activity of fosfomycin transporters. In contrast, we previously described that the cause of fosfomycin resistance in S. maltophilia was the inactivation of enzymes belonging to its central carbon metabolism. To go one step further, here we studied the effects of fosfomycin on the transcriptome of S. maltophilia compared to those of phosphoenolpyruvate—its structural homolog—and glyceraldehyde-3-phosphate—an intermediate metabolite of the mutated route in fosfomycin-resistant mutants. Our results show that transcriptomic changes present a large degree of overlap, including the activation of the cell-wall-stress stimulon. These results indicate that fosfomycin activity and resistance are interlinked with bacterial metabolism. Furthermore, we found that the studied compounds inhibit the expression of the smeYZ efflux pump, which confers intrinsic resistance to aminoglycosides. This is the first description of efflux pump inhibitors that can be used as antibiotic adjuvants to counteract antibiotic resistance in S. maltophilia. Full article

(This article belongs to the Special Issue Antimicrobial Resistance-New Insights)

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15 pages, 3786 KiB

Open AccessArticle

The Evolution of Fluoroquinolone Resistance in Salmonella under Exposure to Sub-Inhibitory Concentration of Enrofloxacin

by Yufeng Gu, Lulu Huang, Cuirong Wu, Junhong Huang, Haihong Hao, Zonghui Yuan and Guyue Cheng

Int. J. Mol. Sci. 2021, 22(22), 12218; https://doi.org/10.3390/ijms222212218 - 11 Nov 2021

Cited by 19 | Viewed by 2704

Abstract

The evolution of resistance in Salmonella to fluoroquinolones (FQs) under a broad range of sub-inhibitory concentrations (sub-MICs) has not been systematically studied. This study investigated the mechanism of resistance development in Salmonella enterica serovar Enteritidis (S. Enteritidis) under sub-MICs of 1/128×MIC to 1/2×MIC of enrofloxacin (ENR), a widely used veterinary FQ. It was shown that the resistance rate and resistance level of S. Enteritidis varied with the increase in ENR concentration and duration of selection. qRT-PCR results demonstrated that the expression of outer membrane porin (OMP) genes, ompC, ompD and ompF, were down-regulated first to rapidly adapt and develop the resistance of 4×MIC, and as the resistance level increased (≥8×MIC), the up-regulated expression of efflux pump genes, acrB, emrB amd mdfA, along with mutations in quinolone resistance-determining region (QRDR) gradually played a decisive role. Cytohubba analysis based on transcriptomic profiles demonstrated that purB, purC, purD, purF, purH, purK, purL, purM, purN and purT were the hub genes for the FQs resistance. The ‘de novo’ IMP biosynthetic process, purine ribonucleoside monophosphate biosynthetic process and purine ribonucleotide biosynthetic process were the top three biological processes screened by MCODE. This study first described the dynamics of FQ resistance evolution in Salmonella under a long-term selection of sub-MICs of ENR in vitro. In addition, this work offers greater insight into the transcriptome changes of S. Enteritidis under the selection of ENR and provides a framework for FQs resistance of Salmonella for further studies. Full article

(This article belongs to the Special Issue Antimicrobial Resistance-New Insights)

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23 pages, 2839 KiB

Open AccessArticle

Novel Insight into the Effects of CpxR on Salmonella enteritidis Cells during the Chlorhexidine Treatment and Non-Stressful Growing Conditions

by Xiaoying Liu, Misara Omar, Kakambi V. Nagaraja, Sagar M. Goyal and Sinisa Vidovic

Int. J. Mol. Sci. 2021, 22(16), 8938; https://doi.org/10.3390/ijms22168938 - 19 Aug 2021

Cited by 4 | Viewed by 2371

Abstract

The development and spread of antibiotics and biocides resistance is a significant global challenge. To find a solution for this emerging problem, the discovery of novel bacterial cellular targets and the critical pathways associated with antimicrobial resistance is needed. In the present study, we investigated the role of the two most critical envelope stress response regulators, RpoE and CpxR, on the physiology and susceptibility of growing Salmonella enterica serovar enteritidis cells using the polycationic antimicrobial agent, chlorhexidine (CHX). It was shown that deletion of the cpxR gene significantly increased the susceptibility of this organism, whereas deletion of the rpoE gene had no effect on the pathogen’s susceptibility to this antiseptic. It has been shown that a lack of the CpxR regulator induces multifaceted stress responses not only in the envelope but also in the cytosol, further affecting the key biomolecules, including DNA, RNA, and proteins. We showed that alterations in cellular trafficking and most of the stress responses are associated with a dysfunctional CpxR regulator during exponential growth phase, indicating that these physiological changes are intrinsically associated with the lack of the CpxR regulator. In contrast, induction of type II toxin-antitoxin systems and decrease of abundances of enzymes and proteins associated with the recycling of muropeptides and resistance to polymixin and cationic antimicrobial peptides were specific responses of the ∆cpxR mutant to the CHX treatment. Overall, our study provides insight into the effects of CpxR on the physiology of S. Enteritidis cells during the exponential growth phase and CHX treatment, which may point to potential cellular targets for the development of an effective antimicrobial agent. Full article

(This article belongs to the Special Issue Antimicrobial Resistance-New Insights)

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15 pages, 2243 KiB

Open AccessArticle

Study on Demethoxycurcumin as a Promising Approach to Reverse Methicillin-Resistance of Staphylococcus aureus

by Qian-Qian Li, Ok-Hwa Kang and Dong-Yeul Kwon

Int. J. Mol. Sci. 2021, 22(7), 3778; https://doi.org/10.3390/ijms22073778 - 6 Apr 2021

Cited by 7 | Viewed by 2538

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) has always been a threatening pathogen. Research on phytochemical components that can replace antibiotics with limited efficacy may be an innovative method to solve intractable MRSA infections. The present study was devoted to investigate the antibacterial activity of the natural compound demethoxycurcumin (DMC) against MRSA and explore its possible mechanism for eliminating MRSA. The minimum inhibitory concentrations (MICs) of DMC against MRSA strains was determined by the broth microdilution method, and the results showed that the MIC of DMC was 62.5 μg/mL. The synergistic effects of DMC and antibiotics were investigated by the checkerboard method and the time–kill assay. The ATP synthase inhibitors were employed to block the metabolic ability of bacteria to explore their synergistic effect on the antibacterial ability of DMC. In addition, western blot analysis and qRT-PCR were performed to detect the proteins and genes related to drug resistance and S. aureus exotoxins. As results, DMC hindered the translation of penicillin-binding protein 2a (PBP2a) and staphylococcal enterotoxin and reduced the transcription of related genes. This study provides experimental evidences that DMC has the potential to be a candidate substance for the treatment of MRSA infections. Full article

(This article belongs to the Special Issue Antimicrobial Resistance-New Insights)

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Review

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17 pages, 2188 KiB

Open AccessReview

Biofilm and Small Colony Variants—An Update on Staphylococcus aureus Strategies toward Drug Resistance

by Henan Guo, Yucui Tong, Junhao Cheng, Zaheer Abbas, Zhongxuan Li, Junyong Wang, Yichen Zhou, Dayong Si and Rijun Zhang

Int. J. Mol. Sci. 2022, 23(3), 1241; https://doi.org/10.3390/ijms23031241 - 22 Jan 2022

Cited by 42 | Viewed by 6393

Abstract

Recently, the drawbacks arising from the overuse of antibiotics have drawn growing public attention. Among them, drug-resistance (DR) and even multidrug-resistance (MDR) pose significant challenges in clinical practice. As a representative of a DR or MDR pathogen, Staphylococcus aureus can cause diversity of infections related to different organs, and can survive or adapt to the diverse hostile environments by switching into other phenotypes, including biofilm and small colony variants (SCVs), with altered physiologic or metabolic characteristics. In this review, we briefly describe the development of the DR/MDR as well as the classical mechanisms (accumulation of the resistant genes). Moreover, we use multidimensional scaling analysis to evaluate the MDR relevant hotspots in the recent published reports. Furthermore, we mainly focus on the possible non-classical resistance mechanisms triggered by the two important alternative phenotypes of the S. aureus, biofilm and SCVs, which are fundamentally caused by the different global regulation of the S. aureus population, such as the main quorum-sensing (QS) and agr system and its coordinated regulated factors, such as the SarA family proteins and the alternative sigma factor σB (SigB). Both the biofilm and the SCVs are able to escape from the host immune response, and resist the therapeutic effects of antibiotics through the physical or the biological barriers, and become less sensitive to some antibiotics by the dormant state with the limited metabolisms. Full article

(This article belongs to the Special Issue Antimicrobial Resistance-New Insights)

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26 pages, 1399 KiB

Open AccessReview

Development of Antimicrobial Phototreatment Tolerance: Why the Methodology Matters

by Aleksandra Rapacka-Zdonczyk, Agata Wozniak, Joanna Nakonieczna and Mariusz Grinholc

Int. J. Mol. Sci. 2021, 22(4), 2224; https://doi.org/10.3390/ijms22042224 - 23 Feb 2021

Cited by 22 | Viewed by 4531

Abstract

Due to rapidly growing antimicrobial resistance, there is an urgent need to develop alternative, non-antibiotic strategies. Recently, numerous light-based approaches, demonstrating killing efficacy regardless of microbial drug resistance, have gained wide attention and are considered some of the most promising antimicrobial modalities. These light-based therapies include five treatments for which high bactericidal activity was demonstrated using numerous in vitro and in vivo studies: antimicrobial blue light (aBL), antimicrobial photodynamic inactivation (aPDI), pulsed light (PL), cold atmospheric plasma (CAP), and ultraviolet (UV) light. Based on their multitarget activity leading to deleterious effects to numerous cell structures—i.e., cell envelopes, proteins, lipids, and genetic material—light-based treatments are considered to have a low risk for the development of tolerance and/or resistance. Nevertheless, the most recent studies indicate that repetitive sublethal phototreatment may provoke tolerance development, but there is no standard methodology for the proper evaluation of this phenomenon. The statement concerning the lack of development of resistance to these modalities seem to be justified; however, the most significant motivation for this review paper was to critically discuss existing dogma concerning the lack of tolerance development, indicating that its assessment is more complex and requires better terminology and methodology. Full article

(This article belongs to the Special Issue Antimicrobial Resistance-New Insights)

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