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Mechanism of aminoglycoside activation, inactivation, and the provability of activity retention. (a) Aminoglycoside confers its bactericidal action by interfering with bacterial mRNA translation upon binding with the 30S ribosomal subunit leading to partial or complete disruption of protein synthesis 27 . (b) Bacteria overcomes aminoglycoside action by producing aminoglycosides modifying enzyme AAC(6′)-Ib which acetylates aminoglycoside by transferring an acetyl group donated by acetyl-CoA to generate 6′-N-aminoglycoside; lacking the ability to bind 30S ribosome thus rendering the antibiotic ineffective. (c) Adjuvant interferes with the acetyl-CoA binding site of AAC; preventing the attachment of acetyl group donor to the enzyme active site, consequently intercepting/blocking the enzymatic modification of aminoglycoside and warranting the execution of aminoglycoside action.
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Interference with antibiotic activity and its inactivation by bacterial modifying enzymes is a prevailing mode of bacterial resistance to antibiotics. Aminoglycoside antibiotics become inactivated by aminoglycoside-6′-N-acetyltransferase-Ib [AAC(6′)-Ib] of gram-negative bacteria which transfers an acetyl group from acetyl-CoA to the antibiotic. The...
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... retain the antibacterial property of aminoglycoside antibiotics, we postulate that blocking the action of AAC(6′)-Ib to prevent antibiotic acetylation can be an effective approach (Fig. 1). Small molecular entities, known as adjuvants, can play significant roles in interfering with the aminoglycoside modifying enzyme AAC(6′)-Ib. An adjuvant may possess very weak or no antibacterial activity on its own but can either obstruct to antibiotic resistance or accelerate antibiotic action. Adjuvant molecule inhibits bacterial ...
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... Aminoglycosides are among the most commonly used antibiotics in the treatment of conjunctivitis by both Gramnegative and Gram-positive bacteria. They bind to the ribosomes and thus interfere with protein synthesis (Ahmed et al. 2020). The ability of bacterial isolates to resist gentamicin through the gene is attributed, perhaps to the repeated use of this antibiotic with bacterial conjunctivitis, which led to a genetic mutation in the aac(3)-I gene, which is one of the genes responsible for resistance to the antibiotic gentamicin, or perhaps to the presence of this gene on plasmids that leads to ease of transmission from one bacteria to another. ...
... acetyltransferase enzyme classified under the family -GNAT (GCN5-related family of N-acetyltransferases). Also, it assists in the acetylation of Mtb's second-line antibiotic, kanamycin, which belongs to the aminoglycoside family of antibiotics [13,14]. Mtb has grown antibiotic-resistant, particularly kanamycin [15,16]. ...
... Various synthetic and plant-based compounds have been identified that inhibit the aminoglycoside acetyltransferase enzyme activity of the Eis protein. [13,14]. In the present study, we identify quercetin as a potential Eis inhibitor thereby preventing the acetylation of kanamycin A. Firstly, we purified recombinant EIS protein as seen in Fig. 1, the protein was induced by 500 mM IPTG. ...
Eis (Enhanced intracellular survival) protein is an aminoglycoside acetyltransferase enzyme classified under the family – GNAT (GCN5-related family of N-acetyltransferases) secreted by Mycobacterium tuberculosis (Mtb). The enzymatic activity of Eis results in the acetylation of kanamycin, thereby impairing the drug’s action. In this study, we expressed and purified recombinant Eis (rEis) to determine the enzymatic activity of Eis and its potential inhibitor. Glide-enhanced precision docking was used to perform molecular docking with chosen ligands. Quercetin was found to interact Eis with a maximum binding affinity of -8.379 kcal/mol as compared to other ligands. Quercetin shows a specific interaction between the positively charged amino acid arginine in Eis and the aromatic ring of quercetin through π-cation interaction. Further, the effect of rEis was studied on the antibiotic activity of kanamycin A in the presence and absence of quercetin. It was observed that the activity of rEis aminoglycoside acetyltransferase decreased with increasing quercetin concentration. The results from the disk diffusion assay confirmed that increasing the concentration of quercetin inhibits the rEis protein activity. In conclusion, quercetin may act as a potential Eis inhibitor.
... Endogenous β-lactamase, such as AmpC β-lactamase, can be induced by benzylpenicillin and imipenem [251], and it can be developed by overexpression of the gene by a mutation [252]. Transferable aminoglycoside-modifying enzymes (AMEs) in Pseudomonas diminish the binding affinity to their target in the bacterial cell, resulting in resistance to aminoglycosides [253]. Colistin is used in the treatment of MDR P. aeruginosa in combination with an anti-Pseudomonas antibiotic such as imipenem, aztreonam, piperacillin, ciprofloxacin, or ceftazidime [254]. ...
... Bacteria can produce enzymes that inhibit antibiotics by changing the antibiotic itself or by changing the target molecule of that antibiotic and making them ineffective in treating the patient's infection (Zakataeva 2021). Among these enzymes, acetylase, adenylase, nucleotidase, phosphorylase, and hydrolase, are mentioned, which limit the effect of antibiotics by using different mechanisms (Li, Zhou, et al. 2021;Ahmed et al. 2020;Magalhães et al. 2020). These microorganisms also resist antibiotics by reducing the permeability of the extracellular membrane of their cells or using efflux pumps to remove antibiotics from the cell entrance (Lamut et al. 2019;Henderson et al. 2021;Sharma, Gupta, and Pathania 2019;Kumar, Lekshmi, et al. 2020). ...
Antibiotic resistance is a significant public health issue, causing illnesses that were once easily treatable with antibiotics to develop into dangerous infections, leading to substantial disability and even death. to help fight this growing threat, scientists are developing new methods and techniques that play a crucial role in treating infections and preventing the inappropriate use of antibiotics. these effective therapeutic methods include phage therapies, quorum-sensing inhibitors, immunotherapeutics, predatory bacteria, antimicrobial adjuvants, haemofiltration, nanoantibiotics, microbiota transplantation, plant-derived antimicrobials, RNA therapy, vaccine development, and probiotics. As a result of the activity of probiotics in the intestine, compounds derived from the structure and metabolism of these bacteria are obtained, called postbiotics, which include multiple agents with various therapeutic applications, especially antimicrobial effects, by using different mechanisms. these compounds have been chosen in particular because they don't promote the spread of antibiotic resistance and don't include substances that can increase antibiotic resistance. this manuscript provides an overview of the novel approaches to preventing antibiotic resistance with emphasis on the various postbiotic metabolites derived from the gut beneficial microbes, their activities, recent related progressions in the food and medical fields, as well as concisely giving an insight into the new concept of postbiotics as "hyperpostbiotic"
... Based on the destructive effects of some adjuvants on aminoglycoside-6 0 -N-acetyltransferase-Ib [AAC(6 0 )-Ib 0 ], studies have explored adjuvants' effect on the activity of aminoglycoside antimicrobials, selection of adjuvants targeting enzymes with higher affinity in vitro, and reactions with bacteria such as Escherichia coli, Klebsiella pneumoniae, and Shigella have been carried out. The results show that adjuvants including zinc pyrithione (ZnPT) and vitamin D significantly increase the antibacterial activity of three aminoglycosides, including antimicrobials-amikacin, gentamicin, and kanamycin, suggesting that the combined use of adjuvants and aminoglycoside antimicrobials is expected to become an emerging field for overcoming bacterial resistance [46]. ...
Antimicrobial resistance (AMR), especially bacterial AMR, poses a global threat to public health and has become a huge obstacle to the effective control of related infectious diseases. Following the golden age of antimicrobials discovery between the 1940s and 1960s, antimicrobial abuse resulted in the rapid emergence of AMR. Nowadays, the problem of AMR has become increasingly serious, and some bacteria have reached the brink of no suitable antimicrobials available. Rapid detection of AMR and level quantification are the prerequisites to control the spread of AMR. Although time-consuming, traditional phenotype-based methods are still the primary methods used in clinical laboratories and are regarded as the gold standard for AMR identification. To offset the limitation of the long turnaround time of phenotype-based methods, molecular detection methods such as polymerase chain reaction (PCR), isothermal amplification, high-throughput sequencing, gene microarray, and mass spectrometry have begun to be widely used and served as important complements to phenotype-based methods. This chapter will describe the advances in the above technologies applied in AMR testing.
... In our quest to identify compounds that inhibit the AAC(6′)-Ib amikacin-disabling action, we recently found that various cations effectively interfere with the enzymatic inactivation 11,12,[19][20][21] . In the case of Zn 2+ , the concentrations needed to inhibit growth of amikacin-resistant cells in the presence of the antibiotic are significantly reduced if the cation is added to the growth media in complex with ionophores [11][12][13][20][21][22] . A very effective complex to reduce amikacin resistance levels in various bacteria is ZnPT, a compound already being researched and repurposed for cancer treatments and that has low toxicity when tested on mice 23,24 . ...
Resistance to amikacin in Gram-negatives is usually mediated by the 6'- N -acetyltransferase type Ib [AAC(6')-Ib], which catalyzes the transfer of an acetyl group from acetyl CoA to the 6' position of the antibiotic molecule. A path to continue the effective use of amikacin against resistant infections is to combine it with inhibitors of the inactivating reaction. We have recently observed that addition of Zn ²⁺ to in-vitro enzymatic reactions, obliterates acetylation of the acceptor antibiotic. Furthermore, when added to amikacin-containing culture medium in complex to ionophores such as pyrithione (ZnPT), it prevents the growth of resistant strains. An undesired property of ZnPT is its poor water-solubility, a problem that currently affects a large percentage of newly designed drugs. Water-solubility helps drugs to dissolve in body fluids and be transported to the target location. We tested a pyrithione derivative described previously (Magda et al. Cancer Res 68:5318–5325, 2008) that contains the amphoteric group di(ethyleneglycol)-methyl ether at position 5 (compound 5002), a modification that enhances the solubility. Compound 5002 in complex with zinc (Zn5002) was tested to assess growth inhibition of amikacin-resistant Acinetobacter baumannii and Klebsiella pneumoniae strains in the presence of the antibiotic. Zn5002 complexes in combination with amikacin at different concentrations completely inhibited growth of the tested strains. However, the concentrations needed to achieve growth inhibition were higher than those required to achieve the same results using ZnPT. Time-kill assays showed that the effect of the combination amikacin/Zn5002 was bactericidal. These results indicate that derivatives of pyrithione with enhanced water-solubility, a property that would make them drugs with better bioavailability and absorption, are a viable option for designing inhibitors of the resistance to amikacin mediated by AAC(6')-Ib, an enzyme commonly found in the clinics.
... Moreover, P. aeruginosa can acquire resistance through a gene mutation which leads to overexpression of AmpC β-lactamases [64]. Pseudomonas resistance to aminoglycosides is mediated by transferable aminoglycoside modifying enzymes (AMEs) that decrease the binding affinity to their target in the bacterial cell [65,66]. The treatment of MDR P. aeruginosa involves colistin in combination with an anti-pseudomonas agent like imipenem, piperacillin, aztreonam, ceftazidime or ciprofloxacin [66,67]. ...
Antibiotics have made it possible to treat bacterial infections such as meningitis and bacteraemia that, prior to their introduction, were untreatable and consequently fatal. Unfortunately, in recent decades overuse and misuse of antibiotics as well as social and economic factors have accelerated the spread of antibiotic-resistant bacteria, making drug treatment ineffective. Currently, at least 700,000 people worldwide die each year due to antimicrobial resistance (AMR). Without new and better treatments, the World Health Organization (WHO) predicts that this number could rise to 10 million by 2050, highlighting a health concern not of secondary importance. In February 2017, in light of increasing antibiotic resistance, the WHO published a list of pathogens that includes the pathogens designated by the acronym ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) to which were given the highest “priority status” since they represent the great threat to humans. Understanding the resistance mechanisms of these bacteria is a key step in the development of new antimicrobial drugs to tackle drug-resistant bacteria. In this review, both the mode of action and the mechanisms of resistance of commonly used antimicrobials will be examined. It also discusses the current state of AMR in the most critical resistant bacteria as determined by the WHO’s global priority pathogens list.
... Recent studies to identify inhibitors of this resistance mechanism showed that zinc interferes with enzymatic inactivation by acetylation catalyzed by the aminoglycoside 6'-N-acetyltransferase type Ib (AAC(6')-Ib) and others [68,193,[196][197][198]. The initial experiments showed that zinc ions very efficiently inhibited AAC(6')-Ib-mediated acetylation of aminoglycosides in vitro [68]. ...
Zinc is a redox-inert trace element that is second only to iron in abundance in biological systems. In cells, zinc is typically buffered and bound to metalloproteins, but it may also exist in a labile or chelatable (free ion) form. Zinc plays a critical role in prokaryotes and eukaryotes, ranging from structural to catalytic to replication to demise. This review discusses the influential properties of zinc on various mechanisms of bacterial proliferation and synergistic action as an antimicrobial element. We also touch upon the significance of zinc among eukaryotic cells and how it may modulate their survival and death through its inhibitory or modulatory effect on certain receptors, enzymes, and signaling proteins. A brief discussion on zinc chelators is also presented, and chelating agents may be used with or against zinc to affect therapeutics against human diseases. Overall, the multidimensional effects of zinc in cells attest to the growing number of scientific research that reveal the consequential prominence of this remarkable transition metal in human health and disease.
... Recent studies to identify inhibitors of this resistance mechanism showed that zinc interferes with enzymatic inactivation by acetylation catalyzed by the aminoglycoside 6'-Nacetyltransferase type Ib [AAC(6')-Ib] and others [72,202,[205][206][207]. The initial experiments showed that zinc ions very efficiently inhibited AAC(6')-Ib-mediated acetylation of aminoglycosides in vitro [72]. ...
Zinc is a redox-inert trace element that is second only to iron in abundance in biological systems. In cells, zinc is typically buffered and bound to metalloproteins, but may also exist as a labile or chelatable (free ion) form. Zinc plays a critical role in prokaryotes and eukaryotes ranging from structural to catalytic to replication to demise. This review discusses the influential properties of zinc on various mechanisms of bacterial proliferation and synergistic action as anti-microbial element. We also touch upon the significance of zinc among eukaryotic cells and how it may modulate their survival and death through its inhibitory or modulatory effect on certain receptors, enzymes, and signaling proteins. A brief discussion on zinc chelators is also presented and chelating agents may be used with or against zinc to affect therapeutics against human diseases. Overall, the multidimensional effects of zinc in cells attest to the growing numbers of scientific research that reveal the consequential prominence of this remarkable transition metal in human health and disease.
Growing resistance to antimicrobial medicines is a critical health problem that must be urgently addressed. Adding to the increasing number of patients that succumb to infections, there are other consequences to the rise in resistance like the compromise of several medical procedures and dental work that are heavily dependent on infection prevention. Since their introduction in the clinics, aminoglycoside antibiotics have been a critical component of the armamentarium to treat infections. Still, the increase in resistance and their side effects led to a decline in their utilization. However, numerous current factors, like the urgent need for antimicrobials and their favorable properties, led to renewed interest in these drugs. While efforts to design new classes of aminoglycosides refractory to resistance mechanisms and with fewer toxic effects are starting to yield new promising molecules, extending the useful life of those already in use is essential. For this, numerous research projects are underway to counter resistance from different angles, like inhibition of expression or activity of resistance components. This review focuses on selected examples of one aspect of this quest, the design or identification of small molecule inhibitors of resistance caused by enzymatic modification of the aminoglycoside. These compounds could be developed as aminoglycoside adjuvants to overcome resistant infections.
