Drown Them in Their Own Garbage: a New Strategy To Reverse Polymyxin Resistance? - Related Documents




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81401.0000Drown Them in Their Own Garbage: a New Strategy To Reverse Polymyxin Resistance? Purcell and colleagues offer new insights into a major mechanism of polymyxin resistance in Gram-negative bacteria (A. B. Purcell, B. J. Voss, and M. S. Trent, J Bacteriol 204:e00498-21, 2022, https://doi.org/10.1128/JB.00498-21). Inactivating a single lipid recycling enzyme causes accumulation of waste lipid by-products that inhibit a key factor responsible for polymyxin resistance.202234843378
981610.9939A two-component system serves as a central hub for connecting energy metabolism and plasmid dissemination in bacteria. Mobile genetic elements such as conjugative plasmids play a key role in the acquisition of antibiotic resistance by pathogenic bacteria. Resistance genes on plasmids can be transferred between bacteria using specialized conjugation machinery. Acinetobacter baumannii, the most common bacterium associated with nosocomial infections, harbors a large conjugative plasmid that encodes a type IV secretion system (T4SS). Feng et al. recently found that the A. baumannii T4SS is specialized for plasmid transfer, suggesting that it may be involved in multidrug resistance (Z. Feng, L. Wang, Q. Guan, X. Chu, and Z.-Q. Luo, mBio e02276-23, 2023, https://doi.org/10.1128/mbio.02276-23), T4SS-encoding genes are shown to be controlled by a versatile GacA/S two-component regulatory system. GacA/S is also found to regulate genes involved in central metabolism. The coordinated regulation of metabolism and plasmid conjugation may be a bacterial strategy for adapting to selective pressure from antibiotics.202338032214
999820.9937mSphere of Influence: Uncovering New Ways To Control Multidrug Resistance by Dissecting Essential Cell Processes. Ana L. Flores-Mireles works in the fields of microbial pathogenesis and development of new therapeutics. In this mSphere of Influence article, she reflects on how the papers "Bacterial cell wall biogenesis is mediated by SEDS and PBP polymerase families functioning semi-autonomously" by H. Cho et al. (Nat Microbiol 1:16172, 2016, https://doi.org/10.1038/nmicrobiol.2016.172) and "A comprehensive, CRISPR-based functional analysis of essential genes in bacteria" by J. M. Peters et al. (Cell 165:1493-1506, 2016, https://doi.org/10.1016/j.cell.2016.05.003) made an impact on her approach to dissecting essential processes to understand microbial pathogenesis in catheter-associated urinary tract infections and generate an effective treatment with reduced likelihood of developing resistance.201931554727
575330.9936Sensitization of Gram-Negative Bacteria to Aminoglycosides with 2-Aminoimidazole Adjuvants. In 2019, five million deaths associated with antimicrobial resistance were reported by The Centers for Disease Control and Prevention (CDC). Acinetobacter baumannii, a Gram-negative bacterial pathogen, is among the list of urgent threats. Previously, we reported 2-aminoimidazole (2-AI) adjuvants that potentiate macrolide activity against A. baumannii. In this study, we identify several of these adjuvants that sensitize A. baumannii to aminoglycoside antibiotics. Lead compounds 1 and 7 lower the tobramycin (TOB) minimum inhibitory concentration (MIC) against the TOB-resistant strain AB5075 from 128 μg/mL to 2 μg/mL at 30 μM. In addition, the lead compounds lower the TOB MIC against the TOB-susceptible strain AB19606 from 4 μg/mL to 1 μg/mL and 0.5 μg/mL, respectively, at 30 μM and 15 μM. The evolution of resistance to TOB and 1 in AB5075 revealed mutations in genes related to protein synthesis, the survival of bacteria under environmental stressors, bacteriophages, and proteins containing Ig-like domains.202337998765
543940.9935Inactivation of macrolides by producers and pathogens. Inactivation, one of the mechanisms of resistance to macrolide, lincosamide and streptogramin (MLS) antibiotics, appears to be fairly rare in clinical isolates in comparison with target site modification or efflux. However, inactivation is one of the major mechanisms through which macrolide-producing organisms avoid self-damage during antibiotic biosynthesis. The inactivation mechanisms for MLS antibiotics in pathogens are mainly hydrolysis, phosphorylation, glycosylation, reduction, deacylation, nucleotidylation, and acetylation. The ere (erythromycin resistance esterase) and mph (macrolide phosphotransferase) genes were originally found in Escherichia coli. Subsequently, Wondrack et al. (Wondrack, L.; Massa, M.; Yang, B.V.; Sutcliffe, J. Antimicrob. Agents Chemother., 1996, 40, 992) reported ere-like activity in Staphylococcus aureus. In addition, a variant of erythromycin esterase was found in Pseudomonas sp. from aquaculture sediment by Kim et al. (Kim, Y.H.; Cha, C.J.; Cerniglia, C.E. FEMS Microbiol. Lett., 2002, 210, 239). Although the mph genes, including mph(K), were first characterized in E. coli, a recent study revealed that S. aureus and Stenotrophomonas maltophilia have mph(C). The mph(C) has a low G+C content, like mph(B), and has high homology with mph(B), but not with mph(A) or mph(K). Consequently, the mph(C) and ere(B) genes seem to have originated from Gram-positive bacteria and been transferred between Gram-positive and Gram-negative bacteria. In this chapter, the genes and the mechanisms involved in the inactivation of MLS antibiotics by antibiotic-producing bacteria are reviewed.200415379733
619050.9934Identifying Escherichia coli genes involved in intrinsic multidrug resistance. Multidrug resistance is a major cause of clinical failure in treating bacterial infections. Increasing evidence suggests that bacteria can resist multiple antibiotics through intrinsic mechanisms that rely on gene products such as efflux pumps that expel antibiotics and special membrane proteins that block the penetration of drug molecules. In this study, Escherichia coli was used as a model system to explore the genetic basis of intrinsic multidrug resistance. A random mutant library was constructed in E. coli EC100 using transposon mutagenesis. The library was screened by growth measurement to identify the mutants with enhanced or reduced resistance to chloramphenicol (Cm). Out of the 4,000 mutants screened, six mutants were found to be more sensitive to Cm and seven were more resistant compared to the wild-type EC100. Mutations in 12 out of the 13 mutants were identified by inverse polymerase chain reaction. Mutants of the genes rob, garP, bipA, insK, and yhhX were more sensitive to Cm compared to the wild-type EC100, while the mutation of rhaB, yejM, dsdX, nagA, yccE, atpF, or htrB led to higher resistance. Overexpression of rob was found to increase the resistance of E. coli biofilms to tobramycin (Tob) by 2.7-fold, while overexpression of nagA, rhaB, and yccE significantly enhanced the susceptibility of biofilms by 2.2-, 2.5-, and 2.1-fold respectively.200818807027
22160.9934Aminoglycosides versus bacteria--a description of the action, resistance mechanism, and nosocomial battleground. Since 1944, we have come a long way using aminoglycosides as antibiotics. Bacteria also have got them selected with hardier resistance mechanisms. Aminoglycosides are aminocyclitols that kill bacteria by inhibiting protein synthesis as they bind to the 16S rRNA and by disrupting the integrity of bacterial cell membrane. Aminoglycoside resistance mechanisms include: (a) the deactivation of aminoglycosides by N-acetylation, adenylylation or O-phosphorylation, (b) the reduction of the intracellular concentration of aminoglycosides by changes in outer membrane permeability, decreased inner membrane transport, active efflux, and drug trapping, (c) the alteration of the 30S ribosomal subunit target by mutation, and (d) methylation of the aminoglycoside binding site. There is an alarming increase in resistance outbreaks in hospital setting. Our review explores the molecular understanding of aminoglycoside action and resistance with an aim to minimize the spread of resistance.200817657587
440970.9933Interventions on Metabolism: Making Antibiotic-Susceptible Bacteria. Antibiotics act on bacterial metabolism, and antibiotic resistance involves changes in this metabolism. Interventions on metabolism with drugs might therefore modify drug susceptibility and drug resistance. In their recent article, Martin Vestergaard et al. (mBio 8:e01114-17, 2017, https://doi.org/10.1128/mBio.01114-17) illustrate the possibility of converting intrinsically resistant bacteria into susceptible ones. They reported that inhibition of a central metabolic enzyme, ATP synthase, allows otherwise ineffective polymyxin antibiotics to act on Staphylococcus aureus The study of the intrinsic resistome of bacterial pathogens has shown that several metabolic genes, including multigene transcriptional regulators, contribute to antibiotic resistance. In some cases, these genes only marginally increase antibiotic resistance, but reduced levels of susceptibility might be critical in the evolution or resistance under low antibiotic concentrations or in the clinical response of highly resistant bacteria. Drug interventions on bacterial metabolism might constitute a critical adjuvant therapy in combination with antibiotics to ensure susceptibility of pathogens with intrinsic or acquired antimicrobial resistance.201729184022
15180.9932Enhanced NADH Metabolism Involves Colistin-Induced Killing of Bacillus subtilis and Paenibacillus polymyxa. The commonly believed mechanism of colistin against Gram-negative bacteria is to cause cell membrane lysis, whereas the mechanism of colistin against Gram-positive bacteria is extremely fragmented. In this study, we found that colistin treatment on Bacillus subtilis WB800, Paenibacillus polymyxa C12 and Paenibacillus polymyxa ATCC842 enhances not only the activities of α-ketoglutaric dehydrogenase and malate dehydrogenase in tricarboxylic acid (TCA) cycle, but also the relative expression levels of their encoding genes. Additionally, the oxaloacetate concentration also increases. Interestingly, the analysis of the relative expression of genes specific for respiratory chain showed that colistin treatment stimulates the respiratory chain in Gram-positive bacteria. Accordingly, the NAD⁺/NADH ratio increases and the oxidative level is then boosted up. As a result, the intensive oxidative damages are induced in Gram-positive bacteria and cells are killed. Notably, both rotenone and oligomycin, respectively, inhibiting NADH dehydrogenase and phosphorylation on respiratory chain can downgrade oxidative stress formation, thus alleviating the colistin-induced killing of Gram-positive cells. Besides, thiourea-based scavenging for reactive oxygen species also rescues the colistin-subjected cells. These data collectively demonstrate that colistin stimulates both TCA cycle and respiratory chain in Gram-positive bacteria, leading to the enhancement of NADH metabolism and resulting in the generation of oxidative damages in Gram-positive cells. Our studies provide a better understanding of antibacterial mechanism of colistin against Gram-positive bacteria, which is important for knowledge on bacterial resistance to colistin happening via the inhibition of respiratory chain and manipulation of its production.201930678237
886890.9932Effects of Stress, Reactive Oxygen Species, and the SOS Response on De Novo Acquisition of Antibiotic Resistance in Escherichia coli. Strategies to prevent the development of antibiotic resistance in bacteria are needed to reduce the threat of infectious diseases to human health. The de novo acquisition of resistance due to mutations and/or phenotypic adaptation occurs rapidly as a result of interactions of gene expression and mutations (N. Handel, J. M. Schuurmans, Y. Feng, S. Brul, and B. H. Ter Kuile, Antimicrob Agents Chemother 58:4371-4379, 2014, http://dx.doi.org/10.1128/AAC.02892-14). In this study, the contribution of several individual genes to the de novo acquisition of antibiotic resistance in Escherichia coli was investigated using mutants with deletions of genes known to be involved in antibiotic resistance. The results indicate that recA, vital for the SOS response, plays a crucial role in the development of antibiotic resistance. Likewise, deletion of global transcriptional regulators, such as gadE or soxS, involved in pH homeostasis and superoxide removal, respectively, can slow the acquisition of resistance to a degree depending on the antibiotic. Deletion of the transcriptional regulator soxS, involved in superoxide removal, slowed the acquisition of resistance to enrofloxacin. Acquisition of resistance occurred at a lower rate in the presence of a second stress factor, such as a lowered pH or increased salt concentration, than in the presence of optimal growth conditions. The overall outcome suggests that a central cellular mechanism is crucial for the development of resistance and that genes involved in the regulation of transcription play an essential role. The actual cellular response, however, depends on the class of antibiotic in combination with environmental conditions.201526666928
206100.9932Review of preclinical studies with ofloxacin. Most Enterobacteriaceae, enteropathogens, and fastidious gram-negative bacteria are highly susceptible to ofloxacin, a new tricyclic fluoroquinolone. Aerobic gram-negative bacilli and gram-positive bacteria are generally not as susceptible to ofloxacin. Obligate anaerobes are generally resistant to ofloxacin, while many mycobacteria, chlamydiae, legionellae, and mycoplasmas are susceptible. Ofloxacin is generally less active than ciprofloxacin against gram-negative bacteria, is similarly active against gram-positive bacteria, mycobacteria, legionellae, and mycoplasmas, and is more active against chlamydiae. However, numerous animal studies have shown these two fluoroquinolones to be similar. Ofloxacin inhibits DNA synthesis, is rapidly bactericidal, and is 1,000-2,400 times more potent against prokaryotic gyrase than against eukaryotic gyrase. The bactericidal effect of ofloxacin is not completely neutralized by inhibitors of protein or RNA synthesis. Resistance to ofloxacin arises from mutations within chromosomal genes involved with DNA gyrase and drug permeation. Selection of resistant mutants by ofloxacin is not as frequent as that seen with nalidixic acid. However, due to the cross-resistance between ofloxacin and other fluoroquinolones, all of these drugs should be used judiciously to preserve their clinical utility.19921554842
4481110.9932New findings in beta-lactam and metronidazole resistant Bacteroides fragilis group. Beta-lactam antibiotics and 5-nitroimidazoles have been extensively used against anaerobic bacteria. However, antibiotic resistance is increasingly common among anaerobic Gram-negative bacilli. The classical mechanisms of resistance to beta-lactams are, (1) production of beta-lactamases; (2) alteration of penicillin-binding proteins (PBPs); and (3) changes in outer membrane permeability to beta-lactams. The 5-nitroimidazole molecule is a prodrug whose activation depends upon reduction of the nitro group in the absence of oxygen. Decreased uptake and altered reduction are believed to be responsible for metronidazole resistance. Five nim genes (A, B, C, D and E) have been identified in Bacteroides fragilis group spp. that confer resistance to 5-nitroimidazole antibiotics. Knowledge of the status and the mechanisms of resistance is critical for both the selection of antimicrobial therapy and the design of new antimicrobial agents. The purpose of this article is to review the mechanisms for and the prevalence of beta-lactam and metronidazole resistance in strains belonging to the B. fragilis group.200212007843
8883120.9932Expression of Meiothermus ruber luxS in E. coli alters the antibiotic susceptibility and biofilm formation. Quorum sensing (QS) and signal molecules used for interspecies communication are well defined in mesophiles, but there is still a plethora of microorganisms in which existence and mechanisms of QS need to be explored, thermophiles being among them. In silico analysis has revealed the presence of autoinducer-2 (AI-2) class of QS signaling molecules in thermophiles, synthesized by LuxS (AI-2 synthase), though the functions of this system are not known. In this study, LuxS of Meiothermus ruber was used for understanding the mechanism and functions of AI-2 based QS among thermophilic bacteria. The luxS gene of M. ruber was expressed in luxS(-) deletion mutant of Escherichia coli. Complementation of luxS resulted in significant AI-2 activity, enhanced biofilm formation, and antibiotic susceptibility. Transcriptome analysis showed significant differential expression of 204 genes between the luxS-complemented and luxS(-) deletion mutant of E. coli. Majority of the genes regulated by luxS belonged to efflux pumps. This elucidation may contribute towards finding novel alternatives against incessant antibiotic resistance in bacteria.Key Points• Expression of luxS in luxS(-)E. coli resulted in increase in biofilm index. • Reduction in the MIC of antibiotics was observed after complementation of luxS. • Downregulation of efflux pump genes was observed after complementation of luxS. • Transcriptome analysis showed that 204 genes were differentially regulated significantly.202032215705
8822130.9932Proteomics Analysis Reveals Bacterial Antibiotics Resistance Mechanism Mediated by ahslyA Against Enoxacin in Aeromonas hydrophila. Bacterial antibiotic resistance is a serious global problem; the underlying regulatory mechanisms are largely elusive. The earlier reports states that the vital role of transcriptional regulators (TRs) in bacterial antibiotic resistance. Therefore, we have investigated the role of TRs on enoxacin (ENX) resistance in Aeromonas hydrophila in this study. A label-free quantitative proteomics method was utilized to compare the protein profiles of the ahslyA knockout and wild-type A. hydrophila strains under ENX stress. Bioinformatics analysis showed that the deletion of ahslyA triggers the up-regulated expression of some vital antibiotic resistance proteins in A. hydrophila upon ENX stress and thereby reduce the pressure by preventing the activation of SOS repair system. Moreover, ahslyA directly or indirectly induced at least 11 TRs, which indicates a complicated regulatory network under ENX stress. We also deleted six selected genes in A. hydrophila that altered in proteomics data in order to evaluate their roles in ENX stress. Our results showed that genes such as AHA_0655, narQ, AHA_3721, AHA_2114, and AHA_1239 are regulated by ahslyA and may be involved in ENX resistance. Overall, our data demonstrated the important role of ahslyA in ENX resistance and provided novel insights into the effects of transcriptional regulation on antibiotic resistance in bacteria.202134168639
4410140.9931Refuse in order to resist: metabolic bottlenecks reduce antibiotic susceptibility. The growth of pathogenic bacteria in the host is a prerequisite for infectious diseases. Antibiotic drugs are used to impair bacterial growth and thereby treat infections. In turn, growth of bacteria is underpinned by their primary metabolism. Thus, it has long been recognized that the activity of antibiotics is determined by the metabolic state of cells. However, only recently researchers have begun to systematically interrogate the links between metabolism and resistance (Jiang et al, ; Lopatkin et al, ; Pinheiro et al, ; Schrader et al, ; Zhao et al, 2021). In their recent study, Lubrano and colleagues (Lubrano et al, 2025) apply an elegant CRISPR-based approach to the model bacterium Escherichia coli to systematically screen the effect of 15,120 mutations in genes that encode for 346 proteins which are required for growth of E. coli (also referred to as ‘essential proteins’). The authors identified a multitude of mutations that reduce the susceptibility against two antibiotics related to two very distinct chemical classes; the β-lactam antibiotic carbenicillin and the aminoglycoside gentamicin. Strikingly, the majority of the identified mutations are directly linked to primary metabolism. The work highlights the importance of metabolism in order to understand antibiotic resistance mechanisms and the ecology and evolution of antibiotic resistance. In addition, the work provides leads to design metabolism-based intervention strategies to mitigate antibiotic resistance.202539966554
9925150.9931Plasmid-mediated quinolone resistance--current knowledge and future perspectives. Quinolones are a group of antimicrobial agents that were serendipitously discovered as byproducts of the synthesis of chloroquine. Chemical modifications, such as the addition of fluorine or piperazine, resulted in the synthesis of third- and fourth-generation fluoroquinolones, with broad-spectrum antimicrobial actions against aerobic or anaerobic, Gram-positive or Gram-negative bacteria. The efficacy and consequent widespread use of quinolones and fluoroquinolones has led to a steady global increase in resistance, mediated via gene mutations, alterations in efflux or cell membranes and plasmid-conferred resistance. The first plasmid-mediated quinolone resistance gene, qnrA1, was detected in 1998. Since then, many other genes have been identified and the underlying mechanisms of resistance have been elucidated. This review provides an overview of quinolone resistance, with particular emphasis on plasmid-mediated resistance.201323569126
186160.9931Plasmid-encoded resistance to arsenic and antimony. Resistance determinants to the toxic oxyanionic salts of arsenic and antimony are found on plasmids of both gram-negative and gram-positive organisms. In most cases these provide resistance to both the oxyanions of +III oxidation state, antimonite and arsenite, and the +V oxidation state, arsenate. In both gram-positive and -negative bacteria, resistance is correlated with efflux of the anions from cells. The determinant from the plasmid R773, isolated from a gram-negative organism, has been studied in detail. It encodes an oxyanion-translocating ATPase with three subunits, a catalytic subunit, the ArsA protein, a membrane subunit, the ArsB subunit, and a specificity factor, the ArsC protein. The first two form a membrane-bound complex with arsenite-stimulated ATPase activity. The determinants from gram-positive bacteria have only the arsB and arsC genes and encode an efflux system without the participation of an ArsA homologue.19921531541
398170.9931The chloramphenicol-inducible catB gene in Agrobacterium tumefaciens is regulated by translation attenuation. Agrobacterium tumefaciens strains C58, A136, and BG53 are chloramphenicol resistant, and each contains the catB gene originally identified by Tennigkeit and Matzuran (Gene 99:113-116, 1991). The chloramphenicol acetyltransferase activity in all of the strains is chloramphenicol inducible. Examination of the catB gene in strain BG53 indicates that it is regulated by an attenuation mechanism similar to translation attenuation that regulates inducible catA genes resident in gram-positive bacteria and the inducible cmlA gene that confers chloramphenicol resistance in Pseudomonas spp.200212107148
219180.9931Mechanisms of bacterial resistance to macrolide antibiotics. Macrolides have been used in the treatment of infectious diseases since the late 1950s. Since that time, a finding of antagonistic action between erythromycin and spiramycin in clinical isolates1 led to evidence of the biochemical mechanism and to the current understanding of inducible or constitutive resistance to macrolides mediated by erm genes containing, respectively, the functional regulation mechanism or constitutively mutated regulatory region. These resistant mechanisms to macrolides are recognized in clinically isolated bacteria. (1) A methylase encoded by the erm gene can transform an adenine residue at 2058 (Escherichia coli equivalent) position of 23S rRNA into an 6N, 6N-dimethyladenine. Position 2058 is known to reside either in peptidyltransferase or in the vicinity of the enzyme region of domain V. Dimethylation renders the ribosome resistant to macrolides (MLS). Moreover, another finding adduced as evidence is that a mutation in the domain plays an important role in MLS resistance: one of several mutations (transition and transversion) such as A2058G, A2058C or U, and A2059G, is usually associated with MLS resistance in a few genera of bacteria. (2) M (macrolide antibiotics)- and MS (macrolide and streptogramin type B antibiotics)- or PMS (partial macrolide and streptogramin type B antibiotics)-phenotype resistant bacteria cause decreased accumulation of macrolides, occasionally including streptogramin type B antibiotics. The decreased accumulation, probably via enhanced efflux, is usually inferred from two findings: (i) the extent of the accumulated drug in a resistant cell increases as much as that in a susceptible cell in the presence of an uncoupling agent such as carbonylcyanide-m-chlorophenylhydrazone (CCCP), 2,4-dinitrophenol (DNP), and arsenate; (ii) transporter proteins, in M-type resistants, have mutual similarity to the 12-transmembrane domain present in efflux protein driven by proton-motive force, and in MS- or PMS-type resistants, transporter proteins have mutual homology to one or two ATP-binding segments in efflux protein driven by ATP. (3) Two major macrolide mechanisms based on antibiotic inactivation are dealt with here: degradation due to hydrolysis of the macrolide lactone ring by an esterase encoded by the ere gene; and modification due to macrolide phosphorylation and lincosamide nucleotidylation mediated by the mph and lin genes, respectively. But enzymatic mechanisms that hydrolyze or modify macrolide and lincosamide antibiotics appear to be relatively rare in clinically isolated bacteria at present. (4) Important developments in macrolide antibiotics are briefly featured. On the basis of information obtained from extensive references and studies of resistance mechanisms to macrolide antibiotics, the mode of action of the drugs, as effectors, and a hypothetical explanation of the regulation of the mechanism with regard to induction of macrolide resistance are discussed.199911810493
226190.9931Resistance mechanisms for Gram-negative bacteria-specific lipopeptides, turnercyclamycins, differ from that of colistin. Bacterial resistance to antibiotics is a crisis. Acinetobacter baumannii is among the CDC urgent threat pathogens in part for this reason. Lipopeptides known as turnercyclamycins are produced by symbiotic bacteria that normally live in marine mollusks, where they may be involved in shaping their symbiotic niche. Turnercyclamycins killed Gram-negative pathogens including drug-resistant Acinetobacter, but how do the mechanisms of resistance compare to other lipopeptide drugs? Here, we define resistance from a truncation of MlaA, a protein involved in regulating bacterial membrane phospholipids. Intriguingly, this resistance mechanism only affected one turnercyclamycin variant, which differed only in two atoms in the lipid tail of the compounds. We could not obtain significant resistance to the second turnercyclamycin variant, which was also effective in an infection model. This study reveals an unexpected subtlety in resistance to lipopeptide antibiotics, which may be useful in the design and development of antibiotics to combat drug resistance.202337882570