Efflux pump inhibitor chlorpromazine effectively increases the susceptibility of Escherichia coli to antimicrobial peptide Brevinin-2CE. - Related Documents




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600901.0000Efflux pump inhibitor chlorpromazine effectively increases the susceptibility of Escherichia coli to antimicrobial peptide Brevinin-2CE. Aim: The response of E. coli ATCC8739 to Brevinin-2CE (B2CE) was evaluated as a strategy to prevent the development of antimicrobial peptide (AMP)-resistant bacteria. Methods: Gene expression levels were detected by transcriptome sequencing and RT-PCR. Target genes were knocked out using CRISPR-Cas9. MIC was measured to evaluate strain resistance. Results: Expression of acrZ and sugE were increased with B2CE stimulation. ATCC8739ΔacrZ and ATCC8739ΔsugE showed twofold and fourfold increased sensitivity, respectively. The survival rate of ATCC8739 was reduced in the presence of B2CE/chlorpromazine (CPZ). Combinations of other AMPs with CPZ also showed antibacterial effects. Conclusion: The results indicate that combinations of AMPs/efflux pump inhibitors (EPIs) may be a potential approach to combat resistant bacteria.202438683168
636610.9972Fluorinated Beta-diketo Phosphorus Ylides Are Novel Efflux Pump Inhibitors in Bacteria. BACKGROUND: One of the most important resistance mechanisms in bacteria is the increased expression of multidrug efflux pumps. To combat efflux-related resistance, the development of new efflux pump inhibitors is essential. MATERIALS AND METHODS: Ten phosphorus ylides were compared based on their MDR-reverting activity in multidrug efflux pump system consisting of the subunits acridine-resistance proteins A and B (AcrA and AcrB) and the multidrug efflux pump outer membrane factor TolC (TolC) of Escherichia coli K-12 AG100 strain and its AcrAB-TolC-deleted strain. Efflux inhibition was assessed by real-time fluorimetry and the inhibition of quorum sensing (QS) was also investigated. The relative gene expression of efflux QS genes was determined by real-time reverse transcriptase quantitative polymerase chain reaction. RESULTS: The most potent derivative was Ph(3)P=C(COC(2)F(5))CHO and its effect was more pronounced on the AcrAB-TolC-expressing E. coli strain, furthermore the most active compounds, Ph(3)P=C(COCF(3))OMe, Ph(3)P=C(COC(2)F(5))CHO and Ph(3)P=C(COCF(3))COMe, reduced the expression of efflux pump and QS genes. CONCLUSION: Phosphorus ylides might be valuable EPI compounds to reverse efflux related MDR in bacteria.201627815466
637120.9966Bioactive compounds from the African medicinal plant Cleistochlamys kirkii as resistance modifiers in bacteria. Cleistochlamys kirkii (Benth) Oliv. (Annonaceae) is a medicinal plant traditionally used in Mozambique to treat infectious diseases. The aim of this study was to find resistance modifiers in C. kirkii for Gram-positive and Gram-negative model bacterial strains. One of the most important resistance mechanisms in bacteria is the efflux pump-related multidrug resistance. Therefore, polycarpol (1), three C-benzylated flavanones (2-4), and acetylmelodorinol (5) were evaluated for their multidrug resistance-reverting activity on methicillin-susceptible and methicillin-resistant Staphylococcus aureus and Escherichia coli AG100 and AG100 A strains overexpressing and lacking the AcrAB-TolC efflux pump system. The combined effects of antibiotics and compounds (2 and 4) were also assessed by using the checkerboard microdilution method in both S. aureus strains. The relative gene expression of the efflux pump genes was determined by real-time reverse transcriptase quantitative polymerase chain reaction. The inhibition of quorum sensing was also investigated. The combined effect of the antibiotics and compound 2 or 4 on the methicillin-sensitive S. aureus resulted in synergism. The most active compounds 2 and 4 increased the expression of the efflux pump genes. These results suggested that C. kirkii constituents could be effective adjuvants in the antibiotic treatment of infections.201829464798
618130.9966Two distinct major facilitator superfamily drug efflux pumps mediate chloramphenicol resistance in Streptomyces coelicolor. Chloramphenicol, florfenicol, and thiamphenicol are used as antibacterial drugs in clinical and veterinary medicine. Two efflux pumps of the major facilitator superfamily encoded by the cmlR1 and cmlR2 genes mediate resistance to these antibiotics in Streptomyces coelicolor, a close relative of Mycobacterium tuberculosis. The transcription of both genes was observed by reverse transcription-PCR. Disruption of cmlR1 decreased the chloramphenicol MIC 1.6-fold, while disruption of cmlR2 lowered the MIC 16-fold. The chloramphenicol MIC of wild-type S. coelicolor decreased fourfold and eightfold in the presence of reserpine and Phe-Arg-beta-naphthylamide, respectively. These compounds are known to potentiate the activity of some antibacterial drugs via efflux pump inhibition. While reserpine is known to potentiate drug activity against gram-positive bacteria, this is the first time that Phe-Arg-beta-naphthylamide has been shown to potentiate drug activity against a gram-positive bacterium.200919687245
904440.9965Impairment of novel non-coding small RNA00203 inhibits biofilm formation and reduces biofilm-specific antibiotic resistance in Acinetobacter baumannii. Small RNAs (sRNAs) are post-transcriptional regulators of many biological processes in bacteria, including biofilm formation and antibiotic resistance. The mechanisms by which sRNA regulates the biofilm-specific antibiotic resistance in Acinetobacter baumannii have not been reported to date. This study aimed to investigate the influence of sRNA00203 (53 nucleotides) on biofilm formation, antibiotic susceptibility, and expression of genes associated with biofilm formation and antibiotic resistance. The results showed that deletion of the sRNA00203-encoding gene decreased the biomass of biofilm by 85%. Deletion of the sRNA00203-encoding gene also reduced the minimum biofilm inhibitory concentrations for imipenem and ciprofloxacin 1024- and 128-fold, respectively. Knocking out of sRNA00203 significantly downregulated genes involved in biofilm matrix synthesis (pgaB), efflux pump production (novel00738), lipopolysaccharide biosynthesis (novel00626), preprotein translocase subunit (secA) and the CRP transcriptional regulator. Overall, the suppression of sRNA00203 in an A. baumannii ST1894 strain impaired biofilm formation and sensitized the biofilm cells to imipenem and ciprofloxacin. As sRNA00203 was found to be conserved in A. baumannii, a therapeutic strategy targeting sRNA00203 may be a potential solution for the treatment of biofilm-associated infections caused by A. baumannii. To the best of the authors' knowledge, this is the first study to show the impact of sRNA00203 on biofilm formation and biofilm-specific antibiotic resistance in A. baumannii.202337315907
617850.9963Involvement of MarR and YedS in carbapenem resistance in a clinical isolate of Escherichia coli from China. A carbapenem-resistant clinical isolate of Escherichia coli, which lacked OmpF and OmpC porins, carried a marR mutation and expressed a functional yedS, a normally nontranslated gene. MarR and YedS are described here as having effects on the ability of this strain to resist carbapenems. Additionally, expression of YedS was regulated by the small RNA MicF in a MarA-dependent way. These findings illustrate how broadly bacteria can mutate within a selective clinical setting, in this case, resistance to carbapenems, by altering three porin genes and one regulatory gene.201323318808
21560.9963Non-antibiotics reverse resistance of bacteria to antibiotics. BACKGROUND: Most clinical isolates that exhibit a multi-drug resistant phenotype owe that resistance to over-expressed efflux pumps. Compounds that are efflux pump inhibitors (EPIs) reduce or reverse resistance to antibiotics to which the bacterial strain is initially resistant. We have evaluated non-antibiotics to reduce resistance of commonly encountered bacterial pathogens to antibiotics. MATERIALS AND METHODS: The effect of non-antibiotics on the susceptibility of bacteria to antibiotics was conducted by minimum inhibition concentration determinations of the antibiotic in the absence and presence of the non-antibiotic. RESULTS: Non-antibiotics such as chlorpromazine, amitryptiline and trans-chlorprothixene are shown to reduce or reverse resistance of a variety of bacteria to antibiotics. CONCLUSION: The results suggest that non-antibiotics may serve as adjuncts to conventional antibiotics for the therapy of problematic antibiotic infections caused by bacteria that owe their resistance to over-expressed efflux pumps.201020952744
637070.9963Inhibitory effects of silybin on the efflux pump of methicillin‑resistant Staphylococcus aureus. Bacterial multidrug resistance efflux systems serve an important role in antimicrobial resistance. Thus, identifying novel and effective efflux pump inhibitors that are safe with no adverse side effects is urgently required. Silybin is a flavonolignan component of the extract from the milk thistle seed. To order to investigate the mechanism by which silybin inhibits the efflux system of methicillin‑resistant Staphylococcus aureus (MRSA), antimicrobial susceptibility testing and the double‑plate method were used to evaluate the effect of silybin on MRSA41577. The ability of silybin to inhibit the efflux of ciprofloxacin from MRSA was evaluated by performing a fluorescence assay. Reverse transcription‑quantitative polymerase chain reaction analysis revealed that silybin reduced the expression of the quinolone resistance protein NorA (norA) and quaternary ammonium resistance proteins A/B (qacA/B) efflux genes in MRSA. This suggested that silybin may effectively inhibit the efflux system of MRSA41577. Compared with the control, MRSA41577 treated with silybin for 16 h exhibited a 36 and 49% reduction in the expression of norA and qacA/B, respectively. Inhibition of the expression of these genes by silybin restored the sensitivity of MRSA41577 to antibiotics, indicating that efflux pump inhibitors, which act by inhibiting the efflux system of MRSA, may disrupt the MRSA resistance to antibiotics, rendering the bacteria sensitive to these drugs.201829845191
77480.9963The 2019 Garrod Lecture: MDR efflux in Gram-negative bacteria-how understanding resistance led to a new tool for drug discovery. The AcrAB-TolC MDR efflux system confers intrinsic MDR and overproduction confers clinically relevant resistance to some antibiotics active against Gram-negative bacteria. The system is made up of three components, namely AcrA, AcrB and TolC, otherwise known as the AcrAB-TolC tripartite system. Inactivation or deletion of a gene encoding one of the constituent proteins, or substitution of a single amino acid in the efflux pump component AcrB that results in loss of efflux function, confers increased antibiotic susceptibility. Clinically relevant resistance can be mediated by a mutation in acrB that changes the way AcrB substrates are transported. However, it is more common that resistant clinical and veterinary isolates overproduce the AcrAB-TolC MDR efflux system. This is due to mutations in genes such as marR and ramR that encode repressors of transcription factors (MarA and RamA, respectively) that when produced activate expression of the acrAB and tolC genes thereby increasing efflux. The Lon protease degrades MarA and RamA to return the level of efflux to that of the WT. Furthermore, the levels of AcrAB-TolC are regulated by CsrA. Studies with fluorescent reporters that report levels of acrAB and regulatory factors allowed the development of a new tool for discovering efflux inhibitors. Screens of the Prestwick Chemical Library and a large library from a collaborating pharmaceutical company have generated a number of candidate compounds for further research.201931626705
20990.9962Targeting quinolone- and aminocoumarin-resistant bacteria with new gyramide analogs that inhibit DNA gyrase. Bacterial DNA gyrase is an essential type II topoisomerase that enables cells to overcome topological barriers encountered during replication, transcription, recombination, and repair. This enzyme is ubiquitous in bacteria and represents an important clinical target for antibacterial therapy. In this paper we report the characterization of three exciting new gyramide analogs-from a library of 183 derivatives-that are potent inhibitors of DNA gyrase and are active against clinical strains of gram-negative bacteria (Escherichia coli, Shigella flexneri, and Salmonella enterica; 3 of 10 wild-type strains tested) and gram-positive bacteria (Bacillus spp., Enterococcus spp., Staphylococcus spp., and Streptococcus spp.; all 9 of the wild-type strains tested). E. coli strains resistant to the DNA gyrase inhibitors ciprofloxacin and novobiocin display very little cross-resistance to these new gyramides. In vitro studies demonstrate that the new analogs are potent inhibitors of the DNA supercoiling activity of DNA gyrase (IC(50)s of 47-170 nM) but do not alter the enzyme's ATPase activity. Although mutations that confer bacterial cells resistant to these new gyramides map to the genes encoding the subunits of the DNA gyrase (gyrA and gyrB genes), overexpression of GyrA, GyrB, or GyrA and GyrB together does not suppress the inhibitory effect of the gyramides. These observations support the hypothesis that the gyramides inhibit DNA gyrase using a mechanism that is unique from other known inhibitors.201730034678
643100.9962Effect of overexpression of small non-coding DsrA RNA on multidrug efflux in Escherichia coli. OBJECTIVES: Several putative and proven drug efflux pumps are present in Escherichia coli. Because many such efflux pumps have overlapping substrate spectra, it is intriguing that bacteria, with their economically organized genomes, harbour such large sets of multidrug efflux genes. To understand how bacteria utilize these multiple efflux pumps, it is important to elucidate the process of pump expression regulation. The aim of this study was to determine a regulator of the multidrug efflux pump in this organism. METHODS: We screened a genomic library of E. coli for genes that decreased drug susceptibility in this organism. The library was developed from the chromosomal DNA of the MG1655 strain, and then the recombinant plasmids were transformed into an acrB-deleted strain. Transformants were screened for resistance to various antibiotics including oxacillin. RESULTS: We found that the multidrug susceptibilities of the acrB-deleted strain were decreased by the overexpression of small non-coding DsrA RNA as well as by the overexpression of known regulators of multidrug efflux pumps. Plasmids carrying the dsrA gene conferred resistance to oxacillin, cloxacillin, erythromycin, rhodamine 6G and novobiocin. DsrA decreased the accumulation of ethidium bromide in E. coli cells. Furthermore, expression of mdtE was significantly increased by dsrA overexpression, and the decreased multidrug susceptibilities modulated by DsrA were dependent on the MdtEF efflux pump. CONCLUSIONS: These results indicate that DsrA modulates multidrug efflux through activation of genes encoding the MdtEF pump in E. coli.201121088020
6299110.9962The effects of antidepressants fluoxetine, sertraline, and amitriptyline on the development of antibiotic resistance in Acinetobacter baumannii. This study investigates the effects of antidepressants fluoxetine, sertraline, and amitriptyline on the development of antibiotic resistance in clinical Acinetobacter baumannii isolates. The isolates were exposed to fluoxetine, sertraline, and amitriptyline for 30 days, respectively. The bacteria that developed resistance to gentamicin, imipenem, colistin, and ciprofloxacin were isolated and expression levels of some antibiotic-resistance genes were determined by quantitative reverse-transcriptase PCR. Before and after the exposure, minimum inhibitory concentration (MIC) values of the bacteria were determined by the microdilution method. The statistical analysis was performed using Student's t test. A time-dependent increase was observed in the number of bacteria that developed resistance and increased the MIC value. After exposure to fluoxetine and sertraline, decreases were observed for efflux and outer membrane porin genes in isolates that developed colistin resistance, and increases were observed in isolates that developed ciprofloxacin resistance. These observations suggest that these antidepressants have similar effects on the development of resistance. While the exposure to fluoxetine did not result in the development of resistance to imipenem, it was observed after exposure to sertraline and amitriptyline, and a common decrease in ompA gene expression was determined in these isolates. To our knowledge, the comparative effects of selected antidepressants on the development of antibiotic resistance in A. baumannii are reported and presented in the literature here for the first time.202235355118
8941120.9962Salicylate reduces the antimicrobial activity of ciprofloxacin against extracellular Salmonella enterica serovar Typhimurium, but not against Salmonella in macrophages. OBJECTIVES: Salicylate, a potent inducer of the MarA activator in Salmonella enterica, is the principal metabolite of aspirin, which is often consumed for medicinal and cosmetic uses. Our research was aimed at testing if salicylate activates the mar regulon in macrophage-associated Salmonella (intracellular bacteria), and investigating its effects on bacterial susceptibility to ciprofloxacin extracellularly and intracellularly. METHODS: J774 macrophages were infected with S. enterica serovar Typhimurium (wild-type and marA null mutant), treated with ciprofloxacin with and without pre-exposure to salicylate, and the surviving bacteria were counted. Similar experiments were conducted with bacteria in broth (extracellular bacteria). Phe-Arg-beta-naphthylamide (PAbetaN) was added to investigate the role of efflux pumps in resistance. The transcriptional regulation of marRAB, acrAB and micF in extracellular and intracellular Salmonella Typhimurium with and without salicylate and ciprofloxacin was investigated using green fluorescent protein as a marker protein and quantitative real time PCR. RESULTS: Pre-exposure of Salmonella to salicylate increased the resistance of extracellular but not intracellular bacteria to ciprofloxacin, although salicylate stimulated the expression of mar genes in intracellular and extracellular bacteria. Using marA mutants and the inhibitor PAbetaN, we showed that the improved resistance in extracellular bacteria is derived from the induction of acrAB by salicylate, which is mediated by MarA. CONCLUSIONS: In intracellular bacteria, the expression of acrAB is already higher when compared with extracellular cells; therefore, salicylate does not result in significant acrAB induction intracellularly and subsequent resistance enhancement. Results show that conclusions raised from extracellular studies cannot be applied to intracellular bacteria, although the systems have similar functions.201020237076
6177130.9962Genes involved in intrinsic antibiotic resistance of Acinetobacter baylyi. Bacterial genes defining intrinsic resistance to antibiotics encode proteins that can be targeted by antibiotic potentiators. To find such genes, a transposon insertion library of Acinetobacter baylyi was screened with subinhibitory concentrations of various antibiotics to find supersusceptible mutants. A DNA microarray printer was used to replica plate 10,000 individual library clones to select mutants unable to grow at 1/10 the MICs of 12 different antibiotics. Transposon insertions in 11 genes were found to cause an eightfold or higher hypersusceptibility to at least one antibiotic. Most of the mutants identified exhibited hypersusceptibility to beta-lactam antibiotics. These included mutants with disruptions of genes encoding proteins involved in efflux (acrB and oprM) as well as genes pertaining to peptidoglycan synthesis and modification (ampD, mpl, and pbpG). However, disruptions of genes encoding proteins with seemingly unrelated functions (gph, argH, hisF, and ACIAD0795) can also render cells hypersusceptible to beta-lactam antibiotics. A knockout of gshA, involved in glutathione biosynthesis, enhanced the susceptibility to metronidazole, while a knockout of recD, involved in recombination and repair, made the bacteria hypersusceptible to ciprofloxacin. Disruption of acrB in Escherichia coli rendered the cells hypersusceptible to several antibiotics. However, knockout mutants of other homologous genes in E. coli showed no significant changes in antibiotic MICs, indicating that the intrinsic resistance genes are species specific.200616940057
6300140.9961Assessing the role of the RND efflux pump in metronidazole resistance of Helicobacter pylori by RT-PCR assay. INTRODUCTION: Metronidazole is a significant antibiotic used for eradication of Helicobacter pylori infections and it is of notice that metronidazole-resistant clinical isolates have been found in high rates worldwide. While the RND family of efflux pumps plays a central role in drug resistance among Gram-negative bacteria, this is questionable for H. pylori. METHODOLOGY: To understand whether TolC homologues of RND pumps contribute to metronidazole resistance in H. pylori isolates, expression of four TolC homologous genes of five resistant clinical isolates exposed to varying concentrations of metronidazole were evaluated by RT-PCR and transcriptional analysis. RESULTS: The results indicate that excess amounts of metronidazole are able to increase the expression level of these genes at the transcriptional stage. CONCLUSIONS: Therefore, it may be hypothesized that use of metronidazole in H. pyori infection can induce metronidazole resistance. Furthermore, the RND family of efflux pumps may contribute to metronidazole resistance in clinical isolates of H. pylori.201121389587
6374150.9961Determining the effect of a new truncated CecropinA-Magenin2 (CE-MA) hybrid peptide on the expression of multidrug-resistant (MDR) Mycobacterium tuberculosis efflux genes. A significant issue in treating bacterial infections is multidrug resistance (MDR) microbes. Drug efflux pumps that reduce cellular drug accumulation are frequently linked to drug resistance. In this study, we set out to determine the effects of CE-MA truncated peptide derivatives against MDR Mycobacterium tuberculosis. Following the assessment of the minimum inhibitory concentrations (MICs) of these peptides against MDR Mycobacterium tuberculosis, a Real-Time PCR was used to examine the expression of six drug efflux pump genes. Next, an MTT assay was performed to test the cytotoxicity of peptides against the A549 cell line. The outcomes demonstrated that CE-MA significantly upregulated gene expression of mmr, and Rv0876c (⩾ 4-fold) than untreated bacteria. Also, under CMt2 stress, significant overexpression of Rv0876c and drrA was seen. However, the results show that upregulation in CMt2-treated bacteria in comparison CE-MA treated bacteria is significantly less for genes tap (P < 0.05), mmr (P < 0.0001), and Rv0876c (P < 0.001). Meanwhile, CMt1 only upregulated the Rv0876c gene and downregulated gene expression of tap, drrA, and mmr. It was also found that all three peptides have no significant effect (P > 0.05) on changing the expression of genes drrC and pstB. Less than 10% of the A549 cell line was susceptible to the toxicity of CMt1 and CMt2 at their MICs range. Our results emphasize the significance of investigating novel peptide-based approaches to combat MDR Mycobacterium tuberculosis and point to these peptides as prospective candidates for additional research.202540178610
775160.9961Time dependent asymptotic analysis of the gene regulatory network of the AcrAB-TolC efflux pump system in gram-negative bacteria. Efflux pumps are a mechanism of intrinsic and evolved resistance in bacteria. If an efflux pump can expel an antibiotic so that its concentration within the cell is below a killing threshold the bacteria are resistant to the antibiotic. Efflux pumps may be specific or they may pump various different substances. This is why many efflux pumps confer multi drug resistance (MDR). In particular over expression of the AcrAB-TolC efflux pump system confers MDR in both Salmonella and Escherichia coli. We consider the complex gene regulation network that controls expression of genes central to controlling the efflux associated genes acrAB and acrEF in Salmonella. We present the first mathematical model of this gene regulatory network in the form of a system of ordinary differential equations. Using a time dependent asymptotic analysis, we examine in detail the behaviour of the efflux system on various different timescales. Asymptotic approximations of the steady states provide an analytical comparison of targets for efflux inhibition.202133694073
6297170.9960Combined effect of bacteriophage and antibiotic on the inhibition of the development of antibiotic resistance in Salmonella typhimurium. This study was designed to evaluate the combined effects of bacteriophage and antibiotic on the reduction of the development of antibiotic-resistance in Salmonella typhimurium LT2. The susceptibilities of S. typhimurium to ciprofloxacin and erythromycin were increased when treated with bacteriophages, showing more than 10% increase in clear zone sizes and greater than twofold decrease in minimum inhibitory concentration values. The growth of S. typhimurium was effectively inhibited by the combination of bacteriophage P22 and ciprofloxacin. The combination treatment effectively reduced the development of antibiotic resistance in S. typhimurium. The relative expression levels of efflux pump-related genes (acrA, acrB, and tolC) and outer membrane-related genes (ompC, ompD, and ompF) were decreased at all treatments. This study provides useful information for designing new antibiotic therapy to control antibiotic-resistant bacteria.201830263855
214180.9960A single-cell drug efflux assay in bacteria by using a directly accessible femtoliter droplet array. Active efflux of drugs, such as antibiotics, from a cell is one of the major mechanisms that cause multi-drug resistance in bacteria. Here we report a method to assess drug efflux activity in individual Escherichia coli cells enclosed and isolated in a directly accessible femtoliter droplet array with a fluorogenic compound. The inhibitory effect of a chemical compound on an exogenously expressed efflux pump system from pathogenic bacteria was easily detected at the single-cell level. We also present a proof-of-principle experiment to screen for the gene encoding a drug efflux pump by collecting individual droplets containing single cells in which the drug efflux activity was restored after introduction of the exogenous gene from pathogenic bacteria. Our approach will be a useful tool to screen novel pump inhibitors and efflux pump genes, and to overcome infectious diseases caused by multi-drug-resistant bacteria.201222814576
210190.9960Development of antisense peptide-peptide nucleic acids against fluoroquinolone-resistant Escherichia coli. BACKGROUND: Fluoroquinolones (FQs) are potent and broad-spectrum antibiotics commonly used to treat MDR bacterial infections, but bacterial resistance to FQs has emerged and spread rapidly around the world. The mechanisms for FQ resistance have been revealed, including one or more mutations in FQ target genes such as DNA gyrase (gyrA) and topoisomerase IV (parC). Because therapeutic treatments for FQ-resistant bacterial infections are limited, it is necessary to develop novel antibiotic alternatives to minimize or inhibit FQ-resistant bacteria. OBJECTIVES: To examine the bactericidal effect of antisense peptide-peptide nucleic acids (P-PNAs) that can block the expression of DNA gyrase or topoisomerase IV in FQ-resistant Escherichia coli (FRE). METHODS: A set of antisense P-PNA conjugates with a bacterial penetration peptide were designed to inhibit the expression of gyrA and parC and were evaluated for their antibacterial activities. RESULTS: Antisense P-PNAs, ASP-gyrA1 and ASP-parC1, targeting the translational initiation sites of their respective target genes significantly inhibited the growth of the FRE isolates. In addition, ASP-gyrA3 and ASP-parC2, which bind to the FRE-specific coding sequence within the gyrA and parC structural genes, respectively, showed selective bactericidal effects against FRE isolates. CONCLUSIONS: Our results demonstrate the potential of targeted antisense P-PNAs as antibiotic alternatives against FQ-resistance bacteria.202337390375