# | Rank | Similarity | Title + Abs. | Year | PMID |
|---|---|---|---|---|---|
| 0 | 1 | 2 | 3 | 4 | 5 |
| 504 | 0 | 0.9886 | Activation of Dithiolopyrrolone Antibiotics by Cellular Reductants. Dithiolopyrrolone (DTP) natural products are broad-spectrum antimicrobial and anticancer prodrugs. The DTP structure contains a unique bicyclic ene-disulfide that once reduced in the cell, chelates metal ions and disrupts metal homeostasis. In this work we investigate the intracellular activation of the DTPs and their resistance mechanisms in bacteria. We show that the prototypical DTP holomycin is reduced by several bacterial reductases and small-molecule thiols in vitro. To understand how bacteria develop resistance to the DTPs, we generate Staphylococcus aureus mutants that exhibit increased resistance to the hybrid DTP antibiotic thiomarinol. From these mutants we identify loss-of-function mutations in redox genes that are involved in DTP activation. This work advances the understanding of how DTPs are activated and informs development of bioreductive disulfide prodrugs. | 2025 | 39665630 |
| 8597 | 1 | 0.9885 | Non-caloric artificial sweeteners exhibit antimicrobial activity against bacteria and promote bacterial evolution of antibiotic tolerance. Non-caloric artificial sweeteners are being widely used as safe table sugar substitutes with highly intensive sweetness but low calories. Previous studies have suggested that some of the sweeteners can alter the gut microbiota composition and promote horizontal transfer of antibiotic resistance genes across bacterial genera. However, little is known about whether these sweeteners could show antibiotic-like antimicrobial activity against bacteria, especially gut relevant bacteria. Whether they could affect evolutional trajectory of antibiotic resistance or tolerance in bacteria is also not clear yet. Here we investigated four commonly used artificial sweeteners (saccharin, sucralose, aspartame, and acesulfame potassium) against both Gram-negative (Escherichia coli and Klebsiella pneumoniae) and positive (Bacillus subtilis) strains. Results show that all four sweeteners exhibit antimicrobial effects on these strains. The antimicrobial mechanism is due to increased reactive oxygen species (ROS) and cell envelope damage. Compared to sucrose and glucose, the treatment of artificial sweeteners stimulates bacterial efflux pumps and promotes bacterial evolution of antibiotic tolerance. Collectively, our finding provides insights into roles of artificial sweeteners in the emergence of antibiotic tolerance and calls for a re-evaluation of risks due to their intensive usage. | 2022 | 35398799 |
| 8353 | 2 | 0.9885 | Adaptive loss of tRNA gene expression leads to phage resistance in a marine Synechococcus cyanobacterium. Synechococcus is a significant primary producer in the oceans, coexisting with cyanophages, which are important agents of mortality. Bacterial resistance against phage infection is a topic of significant interest, yet little is known for ecologically relevant systems. Here we use exogenous gene expression and gene disruption to investigate mechanisms underlying intracellular resistance of marine Synechococcus WH5701 to the Syn9 cyanophage. The restriction-modification and Gabija defence systems possessed by Synechococcus WH5701 did not contribute to resistance. Instead, resistance was primarily driven by insufficient levels of Leu(TAA) tRNA, preventing translation of key phage genes in a passive, intracellular mode of resistance. Restoring cellular tRNA expression rendered the cyanobacterium sensitive to infection. We propose an evolutionary scenario whereby changes in cell codon usage, acquisition of tRNAs by the phage and loss of cell and phage tRNA expression resulted in an effective means of resistance, highlighting the dynamic interplay between bacteria and phages in shaping their co-evolutionary trajectories. | 2025 | 39753669 |
| 8210 | 3 | 0.9884 | Bacterial sensing of antimicrobial peptides. Antimicrobial peptides (AMPs) form a crucial part of human innate host defense, especially in neutrophil phagosomes and on epithelial surfaces. Bacteria have a variety of efficient resistance mechanisms to human AMPs, such as efflux pumps, secreted proteases, and alterations of the bacterial cell surface that are aimed to minimize attraction of the typically cationic AMPs. In addition, bacteria have specific sensors that activate AMP resistance mechanisms when AMPs are present. The prototypical Gram-negative PhoP/PhoQ and the Gram-positive Aps AMP-sensing systems were first described and investigated in Salmonella typhimurium and Staphylococcus epidermidis, respectively. Both include a classical bacterial two-component sensor/regulator system, but show many structural, mechanistic, and functional differences. The PhoP/PhoQ regulon controls a variety of genes not necessarily limited to AMP resistance mechanisms, but apparently aimed to combat innate host defense on a broad scale. In contrast, the staphylococcal Aps system predominantly upregulates AMP resistance mechanisms, namely the D-alanylation of teichoic acids, inclusion of lysyl-phosphati-dylglycerol in the cytoplasmic membrane, and expression of the putative VraFG AMP efflux pump. Notably, both systems are crucial for virulence and represent possible targets for antimicrobial therapy. | 2009 | 19494583 |
| 9123 | 4 | 0.9883 | Antibiotic resistance of bacteria in biofilms. Bacteria that adhere to implanted medical devices or damaged tissue can encase themselves in a hydrated matrix of polysaccharide and protein, and form a slimy layer known as a biofilm. Antibiotic resistance of bacteria in the biofilm mode of growth contributes to the chronicity of infections such as those associated with implanted medical devices. The mechanisms of resistance in biofilms are different from the now familiar plasmids, transposons, and mutations that confer innate resistance to individual bacterial cells. In biofilms, resistance seems to depend on multicellular strategies. We summarise the features of biofilm infections, review emerging mechanisms of resistance, and discuss potential therapies. | 2001 | 11463434 |
| 728 | 5 | 0.9883 | Surviving Reactive Chlorine Stress: Responses of Gram-Negative Bacteria to Hypochlorous Acid. Sodium hypochlorite (NaOCl) and its active ingredient, hypochlorous acid (HOCl), are the most commonly used chlorine-based disinfectants. HOCl is a fast-acting and potent antimicrobial agent that interacts with several biomolecules, such as sulfur-containing amino acids, lipids, nucleic acids, and membrane components, causing severe cellular damage. It is also produced by the immune system as a first-line of defense against invading pathogens. In this review, we summarize the adaptive responses of Gram-negative bacteria to HOCl-induced stress and highlight the role of chaperone holdases (Hsp33, RidA, Cnox, and polyP) as an immediate response to HOCl stress. We also describe the three identified transcriptional regulators (HypT, RclR, and NemR) that specifically respond to HOCl. Besides the activation of chaperones and transcriptional regulators, the formation of biofilms has been described as an important adaptive response to several stressors, including HOCl. Although the knowledge on the molecular mechanisms involved in HOCl biofilm stimulation is limited, studies have shown that HOCl induces the formation of biofilms by causing conformational changes in membrane properties, overproducing the extracellular polymeric substance (EPS) matrix, and increasing the intracellular concentration of cyclic-di-GMP. In addition, acquisition and expression of antibiotic resistance genes, secretion of virulence factors and induction of the viable but nonculturable (VBNC) state has also been described as an adaptive response to HOCl. In general, the knowledge of how bacteria respond to HOCl stress has increased over time; however, the molecular mechanisms involved in this stress response is still in its infancy. A better understanding of these mechanisms could help understand host-pathogen interactions and target specific genes and molecules to control bacterial spread and colonization. | 2020 | 32796669 |
| 580 | 6 | 0.9881 | Acid-tolerant bacteria and prospects in industrial and environmental applications. Acid-tolerant bacteria such as Streptococcus mutans, Acidobacterium capsulatum, Escherichia coli, and Propionibacterium acidipropionici have developed several survival mechanisms to sustain themselves in various acid stress conditions. Some bacteria survive by minor changes in the environmental pH. In contrast, few others adapt different acid tolerance mechanisms, including amino acid decarboxylase acid resistance systems, mainly glutamate-dependent acid resistance (GDAR) and arginine-dependent acid resistance (ADAR) systems. The cellular mechanisms of acid tolerance include cell membrane alteration in Acidithiobacillus thioxidans, proton elimination by F(1)-F(0)-ATPase in Streptococcus pyogenes, biofilm formation in Pseudomonas aeruginosa, cytoplasmic urease activity in Streptococcus mutans, synthesis of the protective cloud of ammonia, and protection or repair of macromolecules in Bacillus caldontenax. Apart from cellular mechanisms, there are several acid-tolerant genes such as gadA, gadB, adiA, adiC, cadA, cadB, cadC, speF, and potE that help the bacteria to tolerate the acidic environment. This acid tolerance behavior provides new and broad prospects for different industrial applications and the bioremediation of environmental pollutants. The development of engineered strains with acid-tolerant genes may improve the efficiency of the transgenic bacteria in the treatment of acidic industrial effluents. KEY POINTS: • Bacteria tolerate the acidic stress by methylating unsaturated phospholipid tail • The activity of decarboxylase systems for acid tolerance depends on pH • Genetic manipulation of acid-tolerant genes improves acid tolerance by the bacteria. | 2023 | 37093306 |
| 298 | 7 | 0.9881 | Molecular analysis of antibiotic tolerance in pneumococci. Widespread pneumococcal resistance and the emergence of tolerance underscores the need to develop new antimicrobials. Uncovering the mechanisms of autolysin activation could yield not only new antibacterial targets but also ways to eradicate a pool of bacteria facilitating the spread of resistance. Although several genes contributing to antibiotic tolerance among pneumococci have been identified, those important in the clinical arena thus far are in a single gene cluster, vex/pep27/vncS/vncR. Mutations within this signal transduction system represent at least one mechanism, which explains tolerance to both penicillin and vancomycin. Since mutations in this locus do not result in tolerance to penicillin alone, there must be other, yet unknown, mutations which account for tolerance to a single antibiotic. In the case of pneumococci, there exist two more autolysins other than LytA suggesting our understanding of how bacteria die is currently only at the beginning. | 2002 | 12195738 |
| 9330 | 8 | 0.9880 | Pneumococcal Extracellular Vesicles Mediate Horizontal Gene Transfer via the Transformation Machinery. Bacterial cells secrete extracellular vesicles (EVs), the function of which is a matter of intense investigation. Here, we show that the EVs secreted by the human pathogen Streptococcus pneumoniae (pneumococcus) are associated with bacterial DNA on their surface and can deliver this DNA to the transformation machinery of competent cells. These findings suggest that EVs contribute to gene transfer in Gram-positive bacteria, and in doing so, may promote the spread of drug resistance genes in the population. | 2023 | 38168155 |
| 8232 | 9 | 0.9880 | Small acid-soluble proteins with intrinsic disorder are required for UV resistance in Myxococcus xanthus spores. Bacterial sporulation in Gram-positive bacteria results in small acid-soluble proteins called SASPs that bind to DNA and prevent the damaging effects of UV radiation. Orthologs of Bacillus subtilis genes encoding SASPs can be found in many sporulating and nonsporulating bacteria, but they are noticeably absent from spore-forming, Gram-negative Myxococcus xanthus. This is despite the fact that M. xanthus can form UV-resistant spores. Here we report evidence that M. xanthus produces its own unique group of low-molecular-weight, acid-soluble proteins that facilitate UV resistance in spores. These M. xanthus-specific SASPs vary depending upon whether spore formation is induced by starvation inside cell aggregations of fruiting bodies or is induced artificially by glycerol induction. Molecular predictions indicate that M. xanthus SASPs may have some association with the cell walls of M. xanthus spores, which may signify a different mechanism of UV protection than that seen in Gram-positive spores. | 2011 | 21515768 |
| 8269 | 10 | 0.9880 | Molecular genetics of Rhizobium Meliloti symbiotic nitrogen fixation. The application of recombinant DNA techniques to the study of symbiotic nitrogen fixation has yielded a growing list of Rhizobium meliloti genes involved in the processes of nodulation, infection thread formation and nitrogenase activity in nodules on the roots of the host plant, Medicago sativa (alfalfa). Interaction with the plant is initiated by genes encoding sensing and motility systems by which the bacteria recognizes and approaches the root. Signal molecules, such as flavonoids, mediate a complex interplay of bacterial and plant nodulation genes leading to entry of the bacteria through a root hair. As the nodule develops, the bacteria proceed inward towards the cortex within infection threads, the formation of which depends on bacterial genes involved in polysaccharide synthesis. Within the cortex, the bacteria enter host cells and differentiate into forms known as bacteroids. Genes which encode and regulate nitrogenase enzyme are expressed in the mature nodule, together with other genes required for import and metabolism of carbon and energy sources offered by the plant. | 1989 | 14542173 |
| 653 | 11 | 0.9880 | Connecting Algal Polysaccharide Degradation to Formaldehyde Detoxification. Formaldehyde is a toxic metabolite that is formed in large quantities during bacterial utilization of the methoxy sugar 6-O-methyl-d-galactose, an abundant monosaccharide in the red algal polysaccharide porphyran. Marine bacteria capable of metabolizing porphyran must therefore possess suitable detoxification systems for formaldehyde. We demonstrate here that detoxification of formaldehyde in the marine Flavobacterium Zobellia galactanivorans proceeds via the ribulose monophosphate pathway. Simultaneously, we show that the genes encoding the key enzymes of this pathway are important for maintaining high formaldehyde resistance. Additionally, these genes are upregulated in the presence of porphyran, allowing us to connect porphyran degradation to the detoxification of formed formaldehyde. | 2022 | 35561127 |
| 703 | 12 | 0.9880 | Bacterial modification of LPS and resistance to antimicrobial peptides. Antimicrobial peptides (APs) are ubiquitous in nature and are thought to kill micro-organisms by affecting membrane integrity. These positively charged peptides interact with negative charges in the LPS of Gram-negative bacteria. A common mechanism of resistance to AP killing is LPS modification. These modifications include fatty acid additions, phosphoethanolamine (PEtN) addition to the core and lipid A regions, 4-amino-4-deoxy-L-arabinose (Ara4N) addition to the core and lipid A regions, acetylation of the O-antigen, and possibly hydroxylation of fatty acids. In Salmonella typhimurium, LPS modifications are induced within host tissues by the two-component regulatory systems PhoPQ and PmrAB. PmrAB activation results in AP resistance by Ara4N addition to lipid A through the activation of at least 8 genes, 7 of which are transcribed as an operon. Loss of this operon and, therefore, Ara4N LPS modification, affects S. typhimurium virulence when administered orally. Transposon mutagenesis of Proteus mirabilis also suggests that LPS modifications affect AP resistance and virulence phenotypes. Therefore, LPS modification in Gram-negative bacteria plays a significant role during infection in resistance to host antimicrobial factors, avoidance of immune system recognition, and maintenance of virulence phenotypes. | 2001 | 11521084 |
| 109 | 13 | 0.9879 | Identification of two putative ATP-cassette genes in Encephalitozoon intestinalis. Currently existing chemotherapeutic compounds are limited and few are effective for treating microsporidiosis. It is possible that resistance of Encephalitozoon to some drugs occurs by efflux mechanisms similar to those previously described for mammalian tumour cells, bacteria or protozoal parasites such as Plasmodium, Leishmania and Entamoeba histolytica. The data in the present study suggest that Encephalitozoon intestinalis contains at least one multidrug resistance gene. We report here two complete sequences EiABC1 and EiABC2, encoding different ATP-binding cassette genes from E. intestinalis, including a P-gp. | 2001 | 11730796 |
| 9526 | 14 | 0.9879 | Will resistance in fungi emerge on a scale similar to that seen in bacteria? Growing numbers of patients receive azoles as prophylaxis or treatment for invasive fungal infections, begging the question of whether emergence of resistance will occur, as has been seen with bacteria. This review examines resistance pathways shared by bacteria and fungi, including alteration and overproduction of drug targets, changes in biosynthetic pathways, and enhanced drug efflux, and assesses whether such commonalities predict increased resistance to azoles. Important differences exist between the two kingdoms, including little, if any, horizontal transfer of extrachromosomal material across fungal species and a longer fungal generation time, thereby slowing vertical transfer of mutant traits. Further, no enzymatic modulation or inactivation of azoles has been reported in fungi. The newer broad-spectrum azoles posaconazole and voriconazole are active against the vast majority of yeasts and moulds and are likely to prevent the emergence of inherently resistant strains. Therefore, the likelihood for an explosion of fungal resistance is relatively low. | 2008 | 18204870 |
| 8273 | 15 | 0.9879 | Targeting quorum sensing and competence stimulation for antimicrobial chemotherapy. Bacterial resistance to antibiotics is now a serious problem, with traditional classes of antibiotics having gradually become ineffective. New drugs are therefore needed to target and inhibit novel pathways that affect the growth of bacteria. An important feature in the survival of bacteria is that they coordinate their efforts together as a colony via secreted auto-inducing molecules. Competence stimulating peptides (CSPs) are among the quorum sensing pheromones involved in this coordination. These peptides activate a two-component system in gram-negative bacteria, binding to and activating a histidine kinase receptor called ComD, which phosphorylates a response regulator called ComE, leading to gene expression and induction of competence. Competent bacteria are able to take up exogenous DNA and incorporate it into their own genome. By this mechanism bacteria are able to acquire and share genes encoding antibiotic resistance. Despite having been studied for over 30 years, this pathway has only recently begun to be explored as a novel approach to modulating bacterial growth. Antagonists of ComD might block the signaling cascade that leads to competence, while overstimulation of ComD might also reduce bacterial growth. One possible approach to inhibiting ComD is to examine peptide sequences of CSPs that activate ComD and attempt to constrain them to bioactive conformations, likely to have higher affinity due to pre-organization for recognition by the receptor. Thus, small molecules that mimic an alpha helical epitope of CSPs, the putative ComD binding domain, have been shown here to inhibit growth of bacteria such as S. pneumoniae. Such alpha helix mimetics may be valuable clues to antibacterial chemotherapeutic agents that utilize a new mechanism to control bacterial growth. | 2012 | 22664089 |
| 8290 | 16 | 0.9879 | Antimicrobial Peptides: Features, Action, and Their Resistance Mechanisms in Bacteria. In recent years, because of increased resistance to conventional antimicrobials, many researchers have started to study the synthesis of new antibiotics to control the disease-causing effects of infectious pathogens. Antimicrobial peptides (AMPs) are among the newest antibiotics; these peptides are integral compounds in all kinds of organisms and play a significant role in microbial ecology, and critically contribute to the innate immunity of organisms by destroying invading microorganisms. Moreover, AMPs may encourage cells to produce chemokines, stimulate angiogenesis, accelerate wound healing, and influence programmed cell death in multicellular organisms. Bacteria differ in their inherent susceptibility and resistance mechanisms to these peptides when responding to the antimicrobial effects of AMPs. Generally, the development of AMP resistance mechanisms is driven by direct competition between bacterial species, and host and pathogen interactions. Several studies have shown diverse mechanisms of bacterial resistance to AMPs, for example, some bacteria produce proteases and trapping proteins; some modify cell surface charge, change membrane fluidity, and activate efflux pumps; and some species make use of biofilms and exopolymers, and develop sensing systems by selective gene expression. A closer understanding of bacterial resistance mechanisms may help in developing novel therapeutic approaches for the treatment of infections caused by pathogenic organisms that are successful in developing extensive resistance to AMPs. Based on these observations, this review discusses the properties of AMPs, their targeting mechanisms, and bacterial resistance mechanisms against AMPs. | 2018 | 29957118 |
| 8599 | 17 | 0.9879 | Artificial sweeteners stimulate horizontal transfer of extracellular antibiotic resistance genes through natural transformation. Antimicrobial resistance has emerged as a global threat to human health. Natural transformation is an important pathway for horizontal gene transfer, which facilitates the dissemination of antibiotic resistance genes (ARGs) among bacteria. Although it is suspected that artificial sweeteners could exert antimicrobial effects, little is known whether artificial sweeteners would also affect horizontal transfer of ARGs via transformation. Here we demonstrate that four commonly used artificial sweeteners (saccharin, sucralose, aspartame, and acesulfame potassium) promote transfer of ARGs via natural transformation in Acinetobacter baylyi ADP1, a model organism for studying competence and transformation. Such phenomenon was also found in a Gram-positive human pathogen Bacillus subtilis and mice faecal microbiome. We reveal that exposure to these sweeteners increases cell envelope permeability and results in an upregulation of genes encoding DNA uptake and translocation (Com) machinery. In addition, we find that artificial sweeteners induce an increase in plasmid persistence in transformants. We propose a mathematical model established to predict the long-term effects on transformation dynamics under exposure to these sweeteners. Collectively, our findings offer insights into natural transformation promoted by artificial sweeteners and highlight the need to evaluate these environmental contaminants for their antibiotic-like side effects. | 2022 | 34465899 |
| 795 | 18 | 0.9879 | Multidrug resistance in Gram-negative bacteria. Broadly specific, so-called multidrug, efflux mechanisms are now known to contribute significantly to intrinsic and acquired multidrug resistance in a number of Gram-negative bacteria, and the boom in bacterial genomics has confirmed the distribution of these systems in all bacteria. This broad distribution of multidrug transporters lends a certain credibility to suggestions that they play a housekeeping role in the cell, beyond any contributions they may make to antimicrobial efflux and resistance. In many instances, these transporters are dispensable, arguing against their carrying out essential cellular functions; nevertheless, the multiplicity of these broadly specific export systems within a given microorganism, often with overlapping substrate specificity, may explain the dispensability of individual exporters. Whatever their intended function, however, their conservation in so many organisms highlights their probable general importance in antimicrobial resistance, particularly in Gram-negative bacteria whose outer membranes work synergistically with many of these export systems to promote drug exclusion. | 2001 | 11587924 |
| 9133 | 19 | 0.9879 | Overcoming antimicrobial resistance by targeting resistance mechanisms. Three mechanisms of antimicrobial resistance predominate in bacteria: antibiotic inactivation, target site modification, and altered uptake by way of restricted entry and/or enhanced efflux. Many of these involve enzymes or transport proteins whose activity can be targeted directly in an attemptto compromise resistance and, thus, potentiate antimicrobial activity. Alternatively, novel agents unaffected by these resistance mechanisms can be developed. Given the ongoing challenge posed by antimicrobial resistance in bacteria, targeting resistance in this way may be our best hope at prolonging the antibiotic era. | 2001 | 11291743 |