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      The antibiotic crisis: On the search for novel antibiotics and resistance mechanisms

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          Abstract

          In the relentless battle for human health, the proliferation of antibiotic‐resistant bacteria has emerged as an impending catastrophe of unprecedented magnitude, potentially driving humanity towards the brink of an unparalleled healthcare crisis. The unyielding advance of antibiotic resistance looms as the foremost threat of the 21st century in clinical, agricultural and environmental arenas. Antibiotic resistance is projected to be the genesis of the next global pandemic, with grim estimations of tens of millions of lives lost annually by 2050. Amidst this impending calamity, our capacity to unearth novel antibiotics has languished, with the past four decades marred by a disheartening ‘antibiotic discovery void’. With nearly 80% of our current antibiotics originating from natural or semi‐synthetic sources, our responsibility is to cast our investigative nets into uncharted ecological niches teeming with microbial strife, the so‐called ‘microbial oases of interactions’. Within these oases of interactions, where microorganisms intensively compete for space and nutrients, a dynamic and ever‐evolving microbial ‘arms race’ is constantly in place. Such a continuous cycle of adaptation and counter‐adaptation is a fundamental aspect of microbial ecology and evolution, as well as the secrets to unique, undiscovered antibiotics, our last bastion against the relentless tide of resistance. In this context, it is imperative to invest in research to explore the competitive realms, like the plant rhizosphere, biological soil crusts, deep sea hydrothermal vents, marine snow and the most modern plastisphere, in which competitive interactions are at the base of the microorganisms' struggle for survival and dominance in their ecosystems: identify novel antibiotic by targeting microbial oases of interactions could represent a ‘missing piece of the puzzle’ in our fight against antibiotic resistance.

          Abstract

          The looming threat of antibiotic‐resistant bacteria is one of the major challenges of the 21 st century across clinical, agricultural, and environmental domains. Despite this crisis, the antibiotic discovery has stagnated, emphasizing the urgent need to explore yet overlooked ecological niches teeming with microbial competition. For istance, by targeting ‘microbial oases of interaction’, such as the plant rhizosphere, biological soil crust, deep‐sea and the more recent plastisphere, there is potential to uncover novel antibiotics. This approach represents a critical aspect of microbial ecology and evolution, offering a promising avenue in the battle against antibiotic resistance.

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          Most cited references51

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          CARD 2020: antibiotic resistome surveillance with the comprehensive antibiotic resistance database

          Abstract The Comprehensive Antibiotic Resistance Database (CARD; https://card.mcmaster.ca) is a curated resource providing reference DNA and protein sequences, detection models and bioinformatics tools on the molecular basis of bacterial antimicrobial resistance (AMR). CARD focuses on providing high-quality reference data and molecular sequences within a controlled vocabulary, the Antibiotic Resistance Ontology (ARO), designed by the CARD biocuration team to integrate with software development efforts for resistome analysis and prediction, such as CARD’s Resistance Gene Identifier (RGI) software. Since 2017, CARD has expanded through extensive curation of reference sequences, revision of the ontological structure, curation of over 500 new AMR detection models, development of a new classification paradigm and expansion of analytical tools. Most notably, a new Resistomes & Variants module provides analysis and statistical summary of in silico predicted resistance variants from 82 pathogens and over 100 000 genomes. By adding these resistance variants to CARD, we are able to summarize predicted resistance using the information included in CARD, identify trends in AMR mobility and determine previously undescribed and novel resistance variants. Here, we describe updates and recent expansions to CARD and its biocuration process, including new resources for community biocuration of AMR molecular reference data.
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            Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2).

            Streptomyces coelicolor is a representative of the group of soil-dwelling, filamentous bacteria responsible for producing most natural antibiotics used in human and veterinary medicine. Here we report the 8,667,507 base pair linear chromosome of this organism, containing the largest number of genes so far discovered in a bacterium. The 7,825 predicted genes include more than 20 clusters coding for known or predicted secondary metabolites. The genome contains an unprecedented proportion of regulatory genes, predominantly those likely to be involved in responses to external stimuli and stresses, and many duplicated gene sets that may represent 'tissue-specific' isoforms operating in different phases of colonial development, a unique situation for a bacterium. An ancient synteny was revealed between the central 'core' of the chromosome and the whole chromosome of pathogens Mycobacterium tuberculosis and Corynebacterium diphtheriae. The genome sequence will greatly increase our understanding of microbial life in the soil as well as aiding the generation of new drug candidates by genetic engineering.
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              Molecular mechanisms of antibiotic resistance.

              Antibiotic-resistant bacteria that are difficult or impossible to treat are becoming increasingly common and are causing a global health crisis. Antibiotic resistance is encoded by several genes, many of which can transfer between bacteria. New resistance mechanisms are constantly being described, and new genes and vectors of transmission are identified on a regular basis. This article reviews recent advances in our understanding of the mechanisms by which bacteria are either intrinsically resistant or acquire resistance to antibiotics, including the prevention of access to drug targets, changes in the structure and protection of antibiotic targets and the direct modification or inactivation of antibiotics.
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                Author and article information

                Contributors
                ramona.marasco@kaust.edu.sa
                Journal
                Microb Biotechnol
                Microb Biotechnol
                10.1111/(ISSN)1751-7915
                MBT2
                Microbial Biotechnology
                John Wiley and Sons Inc. (Hoboken )
                1751-7915
                11 March 2024
                March 2024
                : 17
                : 3 ( doiID: 10.1111/mbt2.v17.3 )
                : e14430
                Affiliations
                [ 1 ] Biological and Environmental Sciences and Engineering Division (BESE) King Abdullah University of Science and Technology (KAUST) Thuwal Saudi Arabia
                [ 2 ] Water Desalination and Reuse Center Biological and Environmental Science and Engineering, King Abdullah University of Science and Technology (KAUST) Thuwal Saudi Arabia
                Author notes
                [*] [* ] Correspondence

                Ramona Marasco, Biological and Environmental Sciences and Engineering Division (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.

                Email: ramona.marasco@ 123456kaust.edu.sa

                Author information
                https://orcid.org/0000-0001-8688-3323
                https://orcid.org/0000-0003-4776-7519
                https://orcid.org/0000-0002-4474-6600
                https://orcid.org/0000-0003-0947-925X
                Article
                MBT214430 MICROBIO-2024-014.R1
                10.1111/1751-7915.14430
                10926060
                38465465
                538c058c-eab6-4e29-b170-e17ad9592ae4
                © 2024 The Authors. Microbial Biotechnology published by Applied Microbiology International and John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 07 February 2024
                : 09 January 2024
                : 13 February 2024
                Page count
                Figures: 2, Tables: 0, Pages: 8, Words: 6244
                Funding
                Funded by: King Abdullah University of Science and Technology (KAUST) , doi 10.13039/501100004052;
                Categories
                Opinion
                Opinion
                Custom metadata
                2.0
                March 2024
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.3.9 mode:remove_FC converted:11.03.2024

                Biotechnology
                Biotechnology

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