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      Overcoming Mycobacterium tuberculosis Drug Resistance: Novel Medications and Repositioning Strategies

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          Abstract

          Mycobacterium tuberculosis, the bacterium responsible for tuberculosis, is a global health concern, affecting millions worldwide. This bacterium has earned a reputation as a formidable adversary due to its multidrug-resistant nature, allowing it to withstand many antibiotics. The development of this drug resistance in Mycobacterium tuberculosis is attributed to innate and acquired mechanisms. In the past, rifampin was considered a potent medication for treating tuberculosis infections. However, the rapid development of resistance to this drug by the bacterium underscores the pressing need for new therapeutic agents. Fortunately, several other medications previously overlooked for tuberculosis treatment are already available in the market. Moreover, several innovative drugs are under clinical investigation, offering hope for more effective treatments. To enhance the effectiveness of these drugs, it is recommended that researchers concentrate on identifying unique target sites within the bacterium during the drug development process. This strategy could potentially circumvent the issues presented by Mycobacterium drug resistance. This review primarily focuses on the characteristics of novel drug resistance mechanisms in Mycobacterium tuberculosis. It also discusses potential medications being repositioned or sourced from novel origins. The ultimate objective of this review is to discover efficacious treatments for tuberculosis that can successfully tackle the hurdles posed by Mycobacterium drug resistance.

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          Mechanisms of Antibiotic Resistance.

          Emergence of resistance among the most important bacterial pathogens is recognized as a major public health threat affecting humans worldwide. Multidrug-resistant organisms have not only emerged in the hospital environment but are now often identified in community settings, suggesting that reservoirs of antibiotic-resistant bacteria are present outside the hospital. The bacterial response to the antibiotic "attack" is the prime example of bacterial adaptation and the pinnacle of evolution. "Survival of the fittest" is a consequence of an immense genetic plasticity of bacterial pathogens that trigger specific responses that result in mutational adaptations, acquisition of genetic material, or alteration of gene expression producing resistance to virtually all antibiotics currently available in clinical practice. Therefore, understanding the biochemical and genetic basis of resistance is of paramount importance to design strategies to curtail the emergence and spread of resistance and to devise innovative therapeutic approaches against multidrug-resistant organisms. In this chapter, we will describe in detail the major mechanisms of antibiotic resistance encountered in clinical practice, providing specific examples in relevant bacterial pathogens.
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            An overview of the antimicrobial resistance mechanisms of bacteria

            Resistance to antimicrobial agents has become a major source of morbidity and mortality worldwide. When antibiotics were first introduced in the 1900's, it was thought that we had won the war against microorganisms. It was soon discovered however, that the microorganisms were capable of developing resistance to any of the drugs that were used. Apparently most pathogenic microorganisms have the capability of developing resistance to at least some antimicrobial agents. The main mechanisms of resistance are: limiting uptake of a drug, modification of a drug target, inactivation of a drug, and active efflux of a drug. These mechanisms may be native to the microorganisms, or acquired from other microorganisms. Understanding more about these mechanisms should hopefully lead to better treatment options for infective diseases, and development of antimicrobial drugs that can withstand the microorganisms attempts to become resistant.
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              A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis.

              The incidence of tuberculosis has been increasing substantially on a worldwide basis over the past decade, but no tuberculosis-specific drugs have been discovered in 40 years. We identified a diarylquinoline, R207910, that potently inhibits both drug-sensitive and drug-resistant Mycobacterium tuberculosis in vitro (minimum inhibitory concentration 0.06 mug/ml). In mice, R207910 exceeded the bactericidal activities of isoniazid and rifampin by at least 1 log unit. Substitution of drugs included in the World Health Organization's first-line tuberculosis treatment regimen (rifampin, isoniazid, and pyrazinamide) with R207910 accelerated bactericidal activity, leading to complete culture conversion after 2 months of treatment in some combinations. A single dose of R207910 inhibited mycobacterial growth for 1 week. Plasma levels associated with efficacy in mice were well tolerated in healthy human volunteers. Mutants selected in vitro suggest that the drug targets the proton pump of adenosine triphosphate (ATP) synthase.
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                Author and article information

                Journal
                ACS Omega
                ACS Omega
                ao
                acsodf
                ACS Omega
                American Chemical Society
                2470-1343
                01 September 2023
                12 September 2023
                : 8
                : 36
                : 32244-32257
                Affiliations
                []Lovely Professional University , Phagwara 144411, Punjab, India
                []C. G. Bhakta Institute of Biotechnology, Uka Tarsadia University , Bardoli 394350, Surat, India
                [§ ]Naran Lala College of Professional and Applied Sciences , Navsari 396450, Gujarat, India
                []Jindal Global Law School, OP Jindal Global University , Sonepat 131001, Haryana, India
                []Center for Plant Science and Biodiversity, University of Swat , Charbagh 19120, Pakistan
                [# ]Department of Genetics and Development, Columbia University Irving Medical Center , New York, New York 10032, United States
                []Department of Botany, Bacha Khan University , Charsadda, 24420 Khyber Pakhtunkhwa, Pakistan
                []Center of Research, Faculty of Engineering, Future University in Egypt , New Cairo 11835, Egypt
                []Department of Biological Sciences, Al Hussein Bin Talal University Ma’an , P.O. Box 20, Ma’an 71111, Jordan
                []Faculty of Pharmacy, Department of Pharmacognosy, Umm Al-Qura University , Makkah 4041-4152, Kingdom of Saudi Arabia
                Author notes
                Author information
                https://orcid.org/0000-0003-2319-2175
                Article
                10.1021/acsomega.3c02563
                10500578
                37720746
                91d1fff9-462a-45c2-b7e1-204e4f1776ed
                © 2023 The Authors. Published by American Chemical Society

                Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works ( https://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 14 April 2023
                : 10 August 2023
                Funding
                Funded by: Umm Al-Qura University, doi 10.13039/501100006701;
                Award ID: 22UQU4350073DSR17
                Categories
                Review
                Custom metadata
                ao3c02563
                ao3c02563

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