Antibiotic Resistance: Linking Phenotypes and Mechanisms

A special issue of Biology (ISSN 2079-7737). This special issue belongs to the section "Microbiology".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 13106

Special Issue Editor


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Guest Editor
Ramón y Cajal Institute for Health Research (IRYCIS), Department of Microbiology, Ramón y Cajal University Hospital, 28034 Madrid, Spain
Interests: antibiotic resistance; resistance mechanisms; phenotypes

Special Issue Information

Dear Colleagues,

The term “antibiotic resistance” implies a phenotype (being resistant to antibiotics) and such phenotype is usually attributed to a “resistance mechanism” (as a mutation in the target of the antibiotic, or the synthesis of an enzyme deactivating the drug, or a pumping out mechanism). However the relation of mechanisms and phenotypes is not necessarily predictable. In fact, the phenotype expected to result from the mechanism might simply not be expressed (at least at the level expected), by a variety of reasons, including gene silencing, recessive condition of the mechanism, insufficient gene copy number, high fitness cost of the expression, inappropriate environmental conditions (studied in ecological genetics), or antagonistic pleiotropy with other resistance gene; also, competition between resistance mechanisms cannot be discarded. Most importantly, the phenotypic expression of a given genetic mechanism might be contingent upon the species (the clones?) where it is located, the growth rate and density of the bacterial population, and, within a particular organism (cell), the expression might be deeply influenced not only by epigenetic interactions, but also by the metabolic status of the cell. In fact the existence of a “mechanism” is the condition for resistance, but there are “processes” required to gain the resistance phenotype. Natural selection of antibiotic resistance is acting on phenotypes, but the ability of selecting the mechanism of resistance, and the carrier organism, is not proportional to the expression of the phenotype; weak (apparently suboptimal) phenotypes could be extremely effective in natural selective conditions. Moreover, the same “mechanism” often provide different phenotypes, not only in terms of level of antibiotic resistance, but on the quality of this resistance (resistance to killing versus resistance to growth inhibition) depending on the antibiotic concentration, the type and physiological features of the target bacterial cell. Indeed the analysis of complex landscape requires of advanced informatic technologies as neural network approach for predicting phenotypes from genotypes The growing dominance of genocentric technology, tending to make synonymous “mechanisms” and “phenotypes” should be modulated by rediscussing the above mentioned asymmetries, and probably others that we do not mention in this summary. This Issue is intending to clarify some of these issues, of critical importance in predicting appropriate antibiotic use and controlling the evolutionary paths and trajectories of antibiotic resistance.

Dr. Fernando Baquero
Guest Editor

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Keywords

  • antibiotic resistance
  • resistance phenotypes
  • resistance mechanisms
  • resistance and metabolism
  • phenotype selection
  • phenotype–genotype
  • phenotype expression
  • epigenetics

Published Papers (3 papers)

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Research

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13 pages, 1161 KiB  
Article
Kanamycin and Ofloxacin Activate the Intrinsic Resistance to Multiple Antibiotics in Mycobacterium smegmatis
by Aleksey A. Vatlin, Olga B. Bekker, Kirill V. Shur, Rustem A. Ilyasov, Petr A. Shatrov, Dmitry A. Maslov and Valery N. Danilenko
Biology 2023, 12(4), 506; https://doi.org/10.3390/biology12040506 - 27 Mar 2023
Cited by 1 | Viewed by 2365
Abstract
Drug resistance (DR) in Mycobacterium tuberculosis is the main problem in fighting tuberculosis (TB). This pathogenic bacterium has several types of DR implementation: acquired and intrinsic DR. Recent studies have shown that exposure to various antibiotics activates multiple genes, including genes responsible for [...] Read more.
Drug resistance (DR) in Mycobacterium tuberculosis is the main problem in fighting tuberculosis (TB). This pathogenic bacterium has several types of DR implementation: acquired and intrinsic DR. Recent studies have shown that exposure to various antibiotics activates multiple genes, including genes responsible for intrinsic DR. To date, there is evidence of the acquisition of resistance at concentrations well below the standard MICs. In this study, we aimed to investigate the mechanism of intrinsic drug cross-resistance induction by subinhibitory concentrations of antibiotics. We showed that pretreatment of M. smegmatis with low doses of antibiotics (kanamycin and ofloxacin) induced drug resistance. This effect may be caused by a change in the expression of transcriptional regulators of the mycobacterial resistome, in particular the main transcriptional regulator whiB7. Full article
(This article belongs to the Special Issue Antibiotic Resistance: Linking Phenotypes and Mechanisms)
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Review

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14 pages, 1162 KiB  
Review
Bacterial Subcellular Architecture, Structural Epistasis, and Antibiotic Resistance
by Fernando Baquero, José-Luis Martínez, Alvaro Sánchez, Miguel D. Fernández-de-Bobadilla, Alvaro San-Millán and Jerónimo Rodríguez-Beltrán
Biology 2023, 12(5), 640; https://doi.org/10.3390/biology12050640 - 23 Apr 2023
Cited by 5 | Viewed by 1829
Abstract
Epistasis refers to the way in which genetic interactions between some genetic loci affect phenotypes and fitness. In this study, we propose the concept of “structural epistasis” to emphasize the role of the variable physical interactions between molecules located in particular spaces inside [...] Read more.
Epistasis refers to the way in which genetic interactions between some genetic loci affect phenotypes and fitness. In this study, we propose the concept of “structural epistasis” to emphasize the role of the variable physical interactions between molecules located in particular spaces inside the bacterial cell in the emergence of novel phenotypes. The architecture of the bacterial cell (typically Gram-negative), which consists of concentrical layers of membranes, particles, and molecules with differing configurations and densities (from the outer membrane to the nucleoid) determines and is in turn determined by the cell shape and size, depending on the growth phases, exposure to toxic conditions, stress responses, and the bacterial environment. Antibiotics change the bacterial cell’s internal molecular topology, producing unexpected interactions among molecules. In contrast, changes in shape and size may alter antibiotic action. The mechanisms of antibiotic resistance (and their vectors, as mobile genetic elements) also influence molecular connectivity in the bacterial cell and can produce unexpected phenotypes, influencing the action of other antimicrobial agents. Full article
(This article belongs to the Special Issue Antibiotic Resistance: Linking Phenotypes and Mechanisms)
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20 pages, 3188 KiB  
Review
Drug Efflux Pump Inhibitors: A Promising Approach to Counter Multidrug Resistance in Gram-Negative Pathogens by Targeting AcrB Protein from AcrAB-TolC Multidrug Efflux Pump from Escherichia coli
by Rawaf Alenazy
Biology 2022, 11(9), 1328; https://doi.org/10.3390/biology11091328 - 08 Sep 2022
Cited by 26 | Viewed by 8306
Abstract
Infections caused by multidrug resistance (MDR) of Gram-negative bacteria have become one of the most severe public health problems worldwide. The main mechanism that confers MDR to bacteria is drug efflux pumps, as they expel a wide range of compounds, especially antibiotics. Among [...] Read more.
Infections caused by multidrug resistance (MDR) of Gram-negative bacteria have become one of the most severe public health problems worldwide. The main mechanism that confers MDR to bacteria is drug efflux pumps, as they expel a wide range of compounds, especially antibiotics. Among the different types of drug efflux pumps, the resistance nodulation division (RND) superfamily confers MDR to various Gram-negative bacteria species. The AcrAB-TolC multidrug efflux pump, from E. coli, a member of RND, is the best-characterized example and an excellent model for understanding MDR because of an abundance of functional and structural data. Small molecule inhibitors that target the AcrAB-TolC drug efflux pump represent a new solution to reversing MDR in Gram-negative bacteria and restoring the efficacy of various used drugs that are clinically relevant to these pathogens, especially in the high shortage of drugs for multidrug-resistant Gram-negative bacteria. This review will investigate solutions of MDR in Gram-negative bacteria by studying the inhibition of the AcrAB-TolC multidrug efflux pump. Full article
(This article belongs to the Special Issue Antibiotic Resistance: Linking Phenotypes and Mechanisms)
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