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After the first aminoglycoside antibiotic streptomycin being applied in clinical practice in the mid-1940s, aminoglycoside antibiotics (AGAs) are widely used to treat clinical bacterial infections and bacterial resistance to AGAs is increasing. The bacterial resistance to AGAs is owed to aminoglycoside modifying enzyme modification, active efflux p...
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... was the first discovered aminoglycoside antibiotic (AGA) to be used for tuberculosis treatment in the mid-1940s ( Schatz et al., 2005). Thereafter, a series of aminoglycoside antibiotics (AGAs) were discovered, including neomycin (1949), gentamicin (1963), tobramycin (1967), sisomycin (1970), amikacin (1972), and plazomicin (2006) (Figure 1), and all were found to have good antibacterial activities not only for gram-negative bacteria but also for some gram-positive bacteria (Becker and Cooper, 2013;Clark and Burgess, 2020). AGAs are composed of amino sugars and aminocyclic alcohols. ...
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... (formerly ACHN-490) is a new type of parenteral drug targeting multidrug-resistant Enterobacteriaceae, including AME-producing bacteria, extended-spectrum beta-lactamase (ESBL) and carbapenemase of microorganisms ( Haedersdal et al., 2016;Castanheira et al., 2018), which was approved by the Food and Drug Administration (FAD) in June 2018 for the treatment of complicated urinary tract infections (cUTI) and pyelonephritis caused by microorganisms (Saravolatz and Stein, 2020). It became the first FDA-approved AGAs after amikacin was approved in 1981, marking the return of AGAs to the market ( Figure 1). In 2013, the Center for Disease Control (CDC) released the first threat report on antibiotic-resistant (AR) bacteria in the United States. ...
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... 2-DOS AGAs such as gentamicin, neomycin B and paromomycin bind to the major groove of helix 69 (H69) of the 23S rRNA of the 50S large subunit, thereby affecting the translation on ribosomes ( Wang et al., 2012;Wasserman et al., 2015). In AGA-resistant P. aeruginosa, changes in the ribosomal helix 69 conformation and deletion of the ribosomal protein UL6 will prevent them from binding to the translation initiation factor IF2, thus interfering with protein synthesis (Halfon et al., 2019). ...
Citations
... In addition, benzothiazolebased compounds have also been reported to exhibit antibacterial activity [45][46][47][48]. Furthermore, antibiotic combination therapy has been argued as a forefront strategy to overcome bacterial drug resistance to antibiotics [49]. Although few studies have revealed the effectiveness of acetaminophen against Staphylococcus aureus [26], no report has shown the mechanistic basis of the antibacterial action of acetaminophen and its derivatives against Shigella species, the pathogens responsible for infectious diarrhea. ...
Diarrhea remains one of the leading causes of mortality worldwide, especially among children. Accumulated evidence has shown that Shigella species are the most prevalent bacteria responsible for diarrhea in developing countries. Antimicrobial therapy is necessary for Shigella infections; however, the development of resistance against current drugs justifies the pressing need to search for alternative medications. In this study, we have applied antibacterial phenotypic screening to identify potent anti-Shigella compounds across a broad chemical diversity, including selected acetaminophen derivatives containing a benzothiazole backbone, and their combination with certain antibiotics. As a result, two acetaminophen derivatives containing a benzothiazole backbone (4a and 4b) inhibited the growth of Shigella flexneri with a common MIC value of 12.5 µg/mL. These compounds were established through a time-kill kinetics study to be potentially bactericidal. Meanwhile, the 2-aminobenzothiazoles (1a and 1b) used for the synthesis of compounds 4 (a and b) were found to be poorly active (MIC: 100 µg/mL) against this pathogen. Combination studies of 4a and 4b with the least effective antibiotics (ceftriaxone and cotrimoxazole) demonstrated synergistic anti-Shigella activity with MIC values decreasing from 12.5 to 0.781 µg/ mL. The present study demonstrates that the azobenzothiazole dyes 4 (a and b) can be repurposed as potential anti-Shigella compounds, thus providing potential chemical pharmacophores for the discovery of drugs against infectious diarrhea caused by Shigella and other enteric pathogens, especially in developing countries.
... In addition, benzothiazolebased compounds have also been reported to exhibit antibacterial activity [45][46][47][48]. Furthermore, antibiotic combination therapy has been argued as a forefront strategy to overcome bacterial drug resistance to antibiotics [49]. Although few studies have revealed the effectiveness of acetaminophen against Staphylococcus aureus [26], no report has shown the mechanistic basis of the antibacterial action of acetaminophen and its derivatives against Shigella species, the pathogens responsible for infectious diarrhea. ...
Diarrhea remains one of the leading causes of mortality worldwide, especially among children. Accumulated evidence has shown that Shigella species are the most prevalent bacteria responsible for diarrhea in developing countries. Antimicrobial therapy is necessary for Shigella infections; however, the development of resistance against current drugs justifies the pressing need to search for alternative medications. In this study, we have applied antibacterial phenotypic screening to identify potent anti-Shigella compounds across a broad chemical diversity, including selected acetaminophen derivatives containing a benzothiazole backbone, and their combination with certain antibiotics. As a result, two acetaminophen derivatives containing a benzothiazole backbone (4a and 4b) inhibited the growth of Shigella flexneri with a common MIC value of 12.5 µg/mL. These compounds were established through a time-kill kinetics study to be potentially bactericidal. Meanwhile, the 2-aminobenzothiazoles (1a and 1b) used for the synthesis of compounds 4 (a and b) were found to be poorly active (MIC: 100 µg/mL) against this pathogen. Combination studies of 4a and 4b with the least effective antibiotics (ceftriaxone and cotrimoxazole) demonstrated synergistic anti-Shigella activity with MIC values decreasing from 12.5 to 0.781 µg/ mL. The present study demonstrates that the azobenzothiazole dyes 4 (a and b) can be repurposed as potential anti-Shigella compounds, thus providing potential chemical pharmacophores for the discovery of drugs against infectious diarrhea caused by Shigella and other enteric pathogens, especially in developing countries.
... Short peptides likely enhance antibiotic effectiveness by targeting the bacterial membrane. This effect is also attributed to the direct antibacterial activity of the peptide (KW-23) through interactions with intercellular targets, such as DNA, after entering the bacteria [32]. With amoxicillin, cefixime, rifampicin, and levofloxacin, synergy was demonstrated against the control strain, but not against MDR P. aeruginosa. ...
Background and Aim: Antibiotic-resistant Pseudomonas aeruginosa poses a serious health threat. This study aimed to investigate the antibacterial activity of peptide KW-23 against drug-resistant P. aeruginosa and its potential for enhancing the efficacy of conventional antibiotics. Materials and Methods: KW-23 was synthesized from nine amino acids, specifically three tryptophans and three lysines. The purity of the substance was analyzed using reverse-phase high-performance liquid chromatography. The peptide was identified through mass spectrometry using electrospray ionization. The minimum inhibitory concentration (MIC) values of KW-23 in combination with conventional antibiotics against control and multidrug-resistant P. aeruginosa were determined utilizing broth microdilution. The erythrocyte hemolytic assay was used to measure toxicity. The KW-23 effect was analyzed using the time-kill curve. Results: The peptide exhibited strong antibacterial activity against control and multidrug-resistant strains of P. aeruginosa, with MICs of 4.5 μg/mL and 20 μg/mL, respectively. At higher concentration of 100 μg/mL, KW-23 exhibited a low hemolytic impact, causing no more than 3% damage to red blood. The cytotoxicity assay demonstrates KW-23’s safety, while the time-kill curve highlights its rapid and sustained antibacterial activity. The combination of KW-23 and gentamicin exhibited synergistic activity against both susceptible and resistant P. aeruginosa, with fractional inhibitory concentration index values of 0.07 and 0.27, respectively. Conclusion: The KW-23 synthesized in the laboratory significantly combats antibiotic-resistant P. aeruginosa. Due to its strong antibacterial properties and low toxicity to cells, KW-23 is a promising alternative to traditional antibiotics in combating multidrug-resistant bacteria. Keywords: antimicrobial resistance, peptides, Pseudomonas aeruginosa, synergism.
... discovery of microbial metabolites (Caldeira et al., 2011). The extracts of strain JSZ06 contained a variety of antibacterial chemicals, the largest group being aminoglycoside antibiotics, which exhibits potent antibacterial activity as has been extensively shown (Khan et al., 2020;Wang et al., 2022). Zimmermann et al. (2016) reported that the synthesis of Neamine antibacterial amphiphilic AG enables the synthesis of new antifungal derivatives. ...
Fusarium wilt, caused by Fusarium oxysporum f. sp. cubense Tropical Race 4 (Foc TR4), poses a significant threat to banana production globally, thereby necessitating effective biocontrol methods to manage this devastating disease. This study investigates the potential of Bacillus siamensis strain JSZ06, isolated from smooth vetch, as a biocontrol agent against Foc TR4. To this end, we conducted a series of in vitro and in vivo experiments to evaluate the antifungal activity of strain JSZ06 and its crude extracts. Additionally, genomic analyses were performed to identify antibiotic synthesis genes, while metabolomic profiling was conducted to characterize bioactive compounds. The results demonstrated that strain JSZ06 exhibited strong inhibitory activity against Foc TR4, significantly reducing mycelial growth and spore germination. Moreover, scanning and transmission electron microscopy revealed substantial ultrastructural damage to Foc TR4 mycelia treated with JSZ06 extracts. Genomic analysis identified several antibiotic synthesis genes, and metabolomic profiling revealed numerous antifungal metabolites. Furthermore, in pot trials, the application of JSZ06 fermentation broth significantly enhanced banana plant growth and reduced disease severity, achieving biocontrol efficiencies of 76.71% and 79.25% for leaves and pseudostems, respectively. In conclusion, Bacillus siamensis JSZ06 is a promising biocontrol agent against Fusarium wilt in bananas, with its dual action of direct antifungal activity and plant growth promotion underscoring its potential for integrated disease management strategies.
... In addition, benzothiazole-based compounds have also been reported to exhibit antibacterial activity [29][30][31][32]. Furthermore, antibiotic combination therapy has been argued as a forefront strategy to overcome bacterial drug resistance to antibiotics [33]. Although few studies have revealed the effectiveness of acetaminophen against Staphylococcus aureus [23], no report has shown the mechanistic basis of the antibacterial action of acetaminophen and its derivatives against Shigella species, the pathogens responsible for infectious diarrhea. ...
Diarrhea remains one of the leading causes of mortality worldwide, especially among children. Recent epidemiological studies conducted in developing countries identified Shigella species as the most predominant pathogenic bacteria responsible for diarrhea. Antimicrobial therapy is necessary for Shigella infections; however, the rapid emergence of resistance against existing an-timicrobials in Shigella spp. poses a serious global health problem. To identify alternative anti-microbial compounds with activity against Shigella species, the pathogens responsible for bacterial diarrhea. In this study, we have applied antibacterial phenotypic screening to identify potent anti-Shigella compounds across a broad chemical diversity, including selected acetaminophen derivatives containing benzothiazoles backbone, and their combination with certain antibiotics. In continuation to our effort in searching potent antimicrobial compounds, we have found this time around that two acetaminophen derivatives containing benzothiazoles backbone (4a and 4b) could inhibit the growth of Shigella flexneri with common MIC value of 12.5 µg/ml. These com-pounds were established through a time-kill kinetics’ study to be bactericidal. Meanwhile, the 2-aminobenzothiazoles (1a and 1b) used for the synthesis of compounds 4 (a & b) were found to be poorly active (MIC: 100 µg/ml) against this pathogen. Combination studies of 4a and 4b with the least susceptible antibiotics (ceftriaxone and cotrimoxazole) demonstrated synergistic an-ti-Shigella activity. The present study demonstrates that the azobenzothiazole dyes 4 (a & b) can be repurposed as potential anti-Shigella compounds, which can serve as scaffolds for the devel-opment of new agents against infectious diarrhea caused by Shigella and other enteric pathogens, especially in developing countries.
... The urge to discover new drugs against multidrug resistance bacteria are inevitably pressing. Combination therapy becomes one of alternative therapeutic methods to treat severe multidrug resistance bacterial infection 51 . Natural compounds are attractive choices to explore for their capacities as antimicrobials and/or adjuvants 9 . ...
Colistin- and carbapenem-resistant Acinetobacter baumannii is a serious multidrug resistant (MDR) bacterium in clinical settings. Discovery of new antibacterial drugs against MDR is facing multiple challenges in drug development. Combination of known antibiotics with a robust adjuvant might be an alternative effective strategy for MDR treatment. In the study herein, we report an antibiotic adjuvant activity of a natural compound panduratin A from fingerroot (Boesenbergia rotunda) as a potent adjuvant to colistin. The present study investigated the antibiotic adjuvant effect of panduratin A against 10 colistin- and carbapenem-resistant A. baumannii. Antibacterial activities were tested by broth microdilution method. Biofilm assay was used to determine the efficacy of panduratin A in biofilm formation inhibition on two representative strains Aci46 and Aci44. Genomic and transcriptomic analyses of colistin- and carbapenem-resistant A. baumannii strains were used to identify potential resistance and tolerance mechanism in the bacteria. Panduratin A-colistin combination showed an increased effect on antibacterial in the A. baumannii. However, panduratin A did not improve the antibacterial activity of imipenem. In addition, panduratin A improves anti-biofilm activity of colistin against Aci44 and Aci46, the colistin- and carbapenem-resistant A. baumannii. Panduratin A markedly enhances bactericidal and anti-biofilm activity of colistin against colistin- resistant A. baumannii. Based on genome comparisons, single nucleotide polymorphism (SNP) patterns in six genes encoding biofilm and lipid A biosynthesis were shared in Aci44 and Aci46. In Aci44, we identified a partial sequence of pmrB encoding a polymyxin resistant component PmrB, whereas a full length of pmrB was observed in Aci46. RNA-seq analyses of Aci44 revealed that panduratin A-colistin combination induced expression of ribosomal proteins and oxidative stress response proteins, whereas iron transporter and MFS-type transporter systems were suppressed. Panduratin A-colistin combination could promote intracellular reactive oxygen species (ROS) accumulation could lead to the cidal effect on colistin-resistant A. baumannii. Combination of panduratin A and colistin showed a significant increase in colistin efficacy against colistin- resistant A. baumannii in comparison of colistin alone. Genomic comparison between Aci44 and Aci46 showed mutations and SNPs that might affect different phenotypes. Additionally, based on RNA-Seq, panduratin A-colistin combination could lead to ROS production and accumulation. These findings confirmed the potency of panduratin as colistin adjuvant against multidrug resistant A. baumannii.
... Beta-lactamases, such as extended-spectrum beta-lactamases (ESBLs) and carbapenemases, hydrolyze beta-lactam rings, rendering antibiotics ineffective [7]. Aminoglycoside-modifying enzymes modify the structure of aminoglycoside antibiotics, reducing their binding affinity to bacterial ribosomes [8]. Target site mutations involve alterations in bacterial cellular structures, such as penicillin-binding proteins or ribosomal subunits, minimizing antibiotic binding and consequently inhibiting their action [9]. ...
The current healthcare environment is at risk due to the facilitated transmission and empowerment of the ESKAPE pathogens, comprising of Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species. These pathogens have posed significant challenges to global public health and the threat has only amplified over time. These multidrug-resistant bacteria have become adept at escaping the effects of conventional antibiotics utilized, leading to severe healthcare-associated infections and compromising immunocompromised patient outcomes to a greater extent. The impact of ESKAPE pathogens is evident in the rapidly rising rates of treatment failures, increased mortality, and elevated healthcare costs. To combat this looming crisis, diverse strategies have been adopted, ranging from the development of novel antimicrobial agents and combination therapies to the implementation of stringent infection control measures. Additionally, there has been a growing emphasis on promoting antimicrobial stewardship programs to optimize the use of existing antibiotics and reduce the selective pressure driving the evolution of resistance. While progress has been made to some extent, the rapid adaptability of these pathogens and the enhancement of antimicrobial resistance mechanisms proves to be a major hurdle yet to be crossed by healthcare professionals. In this viewpoint, the impending threat heralded by the proliferation of ESKAPE pathogens, and the need for a concerted global effort via international collaborations for the assurance of effective and sustainable solutions, are explored. To curb the possibility of outbreaks in the future and to safeguard public health, better preparation via global awareness and defense mechanisms should be given paramount importance.
... This can preserve the efficacy of existing antibiotics and extend their clinical usefulness. 64 However, combination therapy also has some challenges and disadvantages, such as increasing risk of toxicity and adverse effects, increased cost and complexity of treatment, and lack of proper guidelines. 65 Different antibiotics are used for different types of infections and diseases (Tables 1 & 2) caused by both Gram-positive and Gramnegative AMR bacteria with mechanism of action and their current clinical status. ...
Antimicrobial resistance (AMR) poses a significant threat to global health. It makes treating bacterial infections increasingly difficult. AMR arises from various mechanisms of antibiotic resistance including enzymatic inactivation, target alteration, efflux pumps, and decreased permeability. The limited and often ineffective treatments relying on antibiotics and their combinations result in increased morbidity and mortality. Therefore, it is essential to explore alternative methods for combating the challenge of AMR. In recent years, there has been a notable shift towards precision medicine in the battle against AMR. Precision medicine, characterized by its focus on individualized treatment tailored to patients’ specific genetic makeup, offers a paradigm shift in addressing AMR challenges. By pinpointing molecular targets responsible for infection, precision medicine enables more targeted and effective therapies, minimizing the risk of antimicrobial resistance development. Precision medicine can provide an alternative option to combat AMR by focusing on targets responsible for the infection. Bacteriophages and antimicrobial peptides (AMPs) are groups of antimicrobials that can serve as novel alternatives to antibiotics for combating the global antibiotic resistance challenge. They have the potential to be used as targeted therapy. Despite challenges such as limited host range, which refers to the specific bacteria they can infect, and regulatory concerns related to their approval and usage, bacteriophages have proven effective against bacteria causing infections. Meanwhile, AMPs provide a potential treatment approach against antibiotic-resistant bacteria due to their low molecular weight and broad-spectrum antimicrobial activity. AMPs can serve as a first line of defense against microorganisms. When used alone or combined with other biomaterials to increase therapeutic action, they can serve as a first line of defense against microorganisms. This review article aims to provide a comprehensive overview of the current understanding and clinical potential of bacteriophages and AMPs as alternatives to conventional antibiotics in addressing the pressing challenge of AMR.
... This condition is generally easily satisfied since resistance enzymes are produced in large quantities (N. Wang et al., 2022). ...
Aminoglycosides are a group of broad-spectrum antibiotics that progress the formation of antibiotic-resistant strains. As many microbes have the capability to encounter them with their diverse defense mechanisms, this sheds light on the vulnerability of aminoglycosides as antibiotics. Consistent use of numerous antibiotics has resulted in MDR strains, becoming the most sensitive and high-priority concern. The microbial resistance against aminoglycosides is due to AMEs which improvise the chemical structure of aminoglycosides and ceases the ability of the antibiotic to bind to its natural target site. Evolutionary processes make AMEs capable of resisting most natural and semi-synthetic antibiotics. Consequently, constructing AME inhibition strategies that may block the modification of aminoglycosides by AMEs to counter the problem of multi-drug-resistant bacteria. This chapter provides insight into understanding aminoglycosides and AME interactions, which play a pivotal role in developing inhibitory strategies. It may be helpful to counter the threat of MDR.
... Advancements in antimicrobial treatments are needed to replace and augment current therapies due to increased bacterial resistance (O'Neill, 2016). Combination therapies are used predominantly in cancer chemotherapy and cardiovascular diseases (Bhatia et al., 2020;Chen & Lahav, 2016;Guerrero-García & Rubio-Guerra, 2018), however, such therapies can be also applied to antimicrobial treatments offering opportunities to breathe new life or extend the reach of existing drugs (Evans et al., 2022;Wang et al., 2022). ...
Increasing antimicrobial drug resistance represents a global existential threat. Infection is a particular problem in immunocompromised individuals, such as patients undergoing cancer chemotherapy, due to the targeting of rapidly dividing cells by antineoplastic agents. We recently developed a strategy that targets bacterial nucleotide excision DNA repair (NER) to identify compounds that act as antimicrobial sensitizers specific for patients undergoing cancer chemotherapy. Building on this, we performed a virtual drug screening of a ~120,000 compound library against the key NER protein UvrA. From this, numerous target compounds were identified and of those a candidate compound, Bemcentinib (R428), showed a strong affinity toward UvrA. This NER protein possesses four ATPase sites in its dimeric state, and we found that Bemcentinib could inhibit UvrA's ATPase activity by ~90% and also impair its ability to bind DNA. As a result, Bemcentinib strongly diminishes NER's ability to repair DNA in vitro. To provide a measure of in vivo activity we discovered that the growth of Escherichia coli MG1655 was significantly inhibited when Bemcentinib was combined with the DNA damaging agent 4‐NQO, which is analogous to UV. Using the clinically relevant DNA‐damaging antineoplastic cisplatin in combination with Bemcentinib against the urological sepsis‐causing E. coli strain EC958 caused complete growth inhibition. This study offers a novel approach for the potential development of new compounds for use as adjuvants in antineoplastic therapy.
