Fosfomycin and Tobramycin in Combination Downregulate Nitrate Reductase GenesnarGandnarH, Resulting in Increased Activity against Pseudomonas aeruginosa under Anaerobic Conditions

ABSTRACTThe activity of aminoglycosides, which are used to treatPseudomonas aeruginosarespiratory infection in cystic fibrosis (CF) patients, is reduced under the anaerobic conditions that reflect the CF lungin vivo. In contrast, a 4:1 (wt/wt) combination of fosfomycin and tobramycin (F:T), which is under investigation for use in the treatment of CF lung infection, has increased activity againstP. aeruginosaunder anaerobic conditions. The aim of this study was to elucidate the mechanisms underlying the increased activity of F:T under anaerobic conditions. Microarray analysis was used to identify the transcriptional basis of increased F:T activity under anaerobic conditions, and key findings were confirmed by microbiological tests, including nitrate utilization assays, growth curves, and susceptibility testing. Notably, growth in subinhibitory concentrations of F:T, but not tobramycin or fosfomycin alone, significantly downregulated (P< 0.05) nitrate reductase genesnarGandnarH, which are essential for normal anaerobic growth ofP. aeruginosa. Under anaerobic conditions, F:T significantly decreased (P< 0.001) nitrate utilization inP. aeruginosastrains PAO1, PA14, and PA14lasR::Gm, a mutant known to exhibit increased nitrate utilization. A similar effect was observed with two clinicalP. aeruginosaisolates. Growth curves indicate that nitrate reductase transposon mutants had reduced growth under anaerobic conditions, with these mutants also having increased susceptibility to F:T compared to the wild type under similar conditions. The results of this study suggest that downregulation of nitrate reductase genes resulting in reduced nitrate utilization is the mechanism underlying the increased activity of F:T under anaerobic conditions.

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Phenazines Regulate Nap-Dependent Denitrification inPseudomonas aeruginosaBiofilms

Journal of Bacteriology ◽

10.1128/jb.00031-18 ◽

2018 ◽

Vol 200 (9) ◽

Cited By ~ 16

Author(s):

Yu-Cheng Lin ◽

Matthew D. Sekedat ◽

William Cole Cornell ◽

Gustavo M. Silva ◽

Chinweike Okegbe ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Nitrate Reductase ◽

Electron Acceptor ◽

Bacterial Infections ◽

Redox State ◽

Reductase Activity ◽

Anaerobic Growth ◽

Bet Hedging ◽

Terminal Electron Acceptor ◽

Content Type

ABSTRACTMicrobes in biofilms face the challenge of substrate limitation. In particular, oxygen often becomes limited for cells inPseudomonas aeruginosabiofilms growing in the laboratory or during host colonization. Previously we found that phenazines, antibiotics produced byP. aeruginosa, balance the intracellular redox state of cells in biofilms. Here, we show that genes involved in denitrification are induced in phenazine-null (Δphz) mutant biofilms grown under an aerobic atmosphere, even in the absence of nitrate. This finding suggests that resident cells employ a bet-hedging strategy to anticipate the potential availability of nitrate and counterbalance their highly reduced redox state. Consistent with our previous characterization of aerobically grown colonies supplemented with nitrate, we found that the pathway that is induced in Δphzmutant colonies combines the nitrate reductase activity of the periplasmic enzyme Nap with the downstream reduction of nitrite to nitrogen gas catalyzed by the enzymes Nir, Nor, and Nos. This regulatory relationship differs from the denitrification pathway that functions under anaerobic growth, with nitrate as the terminal electron acceptor, which depends on the membrane-associated nitrate reductase Nar. We identified the sequences in the promoter regions of thenapandniroperons that are required for the effects of phenazines on expression. We also show that specific phenazines have differential effects onnapgene expression. Finally, we provide evidence that individual steps of the denitrification pathway are catalyzed at different depths within aerobically grown biofilms, suggesting metabolic cross-feeding between community subpopulations.IMPORTANCEAn understanding of the unique physiology of cells in biofilms is critical to our ability to treat fungal and bacterial infections. Colony biofilms of the opportunistic pathogenPseudomonas aeruginosagrown under an aerobic atmosphere but without nitrate express a denitrification pathway that differs from that used for anaerobic growth. We report that the components of this pathway are induced by electron acceptor limitation and that they are differentially expressed over the biofilm depth. These observations suggest that (i)P. aeruginosaexhibits “bet hedging,” in that it expends energy and resources to prepare for nitrate availability when other electron acceptors are absent, and (ii) cells in distinct biofilm microniches may be able to exchange substrates to catalyze full denitrification.

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Anaerobic Growth of Haloarchaeon Haloferax volcanii by Denitrification Is Controlled by the Transcription Regulator NarO

Journal of Bacteriology ◽

10.1128/jb.00833-15 ◽

2016 ◽

Vol 198 (7) ◽

pp. 1077-1086 ◽

Cited By ~ 17

Author(s):

Tatsuya Hattori ◽

Hiromichi Shiba ◽

Ken-ichi Ashiki ◽

Takuma Araki ◽

Yoh-kow Nagashima ◽

...

Keyword(s):

Nitrate Reductase ◽

Promoter Sequence ◽

Haloferax Volcanii ◽

Anaerobic Growth ◽

Halophilic Archaeon ◽

Anaerobic Conditions ◽

Homologous Proteins ◽

Promoter Assay ◽

Content Type ◽

Extremely Halophilic Archaeon

ABSTRACTThe extremely halophilic archaeonHaloferax volcaniigrows anaerobically by denitrification. A putative DNA-binding protein, NarO, is encoded upstream of the respiratory nitrate reductase gene ofH. volcanii. Disruption of thenarOgene resulted in a loss of denitrifying growth ofH. volcanii, and the expression of the recombinant NarO recovered the denitrification capacity. A novel CXnCXCX7C motif showing no remarkable similarities with known sequences was conserved in the N terminus of the NarO homologous proteins found in the haloarchaea. Restoration of the denitrifying growth was not achieved by expression of any mutant NarO in which any one of the four conserved cysteines was individually replaced by serine. A promoter assay experiment indicated that thenarOgene was usually transcribed, regardless of whether it was cultivated under aerobic or anaerobic conditions. Transcription of the genes encoding the denitrifying enzymes nitrate reductase and nitrite reductase was activated under anaerobic conditions. A putativeciselement was identified in the promoter sequence of haloarchaeal denitrifying genes. These results demonstrated a significant effect of NarO, probably due to its oxygen-sensing function, on the transcriptional activation of haloarchaeal denitrifying genes.IMPORTANCEH. volcaniiis an extremely halophilic archaeon capable of anaerobic growth by denitrification. The regulatory mechanism of denitrification has been well understood in bacteria but remains unknown in archaea. In this work, we show that the helix-turn-helix (HTH)-type regulator NarO activates transcription of the denitrifying genes ofH. volcaniiunder anaerobic conditions. A novel cysteine-rich motif, which is critical for transcriptional regulation, is present in NarO. A putativeciselement was also identified in the promoter sequence of the haloarchaeal denitrifying genes.

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Exogenous Alginate Protects Staphylococcus aureus from Killing by Pseudomonas aeruginosa

Journal of Bacteriology ◽

10.1128/jb.00559-19 ◽

2019 ◽

Vol 202 (8) ◽

Cited By ~ 2

Author(s):

Courtney E. Price ◽

Dustin G. Brown ◽

Dominique H. Limoli ◽

Vanessa V. Phelan ◽

George A. O’Toole

Keyword(s):

Staphylococcus Aureus ◽

Pseudomonas Aeruginosa ◽

Physical Space ◽

Late Time ◽

Protective Effects ◽

Content Type ◽

Alginate Production ◽

The Impact

ABSTRACT Cystic fibrosis (CF) patients chronically infected with both Pseudomonas aeruginosa and Staphylococcus aureus have worse health outcomes than patients who are monoinfected with either P. aeruginosa or S. aureus. We showed previously that mucoid strains of P. aeruginosa can coexist with S. aureus in vitro due to the transcriptional downregulation of several toxic exoproducts typically produced by P. aeruginosa, including siderophores, rhamnolipids, and HQNO (2-heptyl-4-hydroxyquinoline N-oxide). Here, we demonstrate that exogenous alginate protects S. aureus from P. aeruginosa in both planktonic and biofilm coculture models under a variety of nutritional conditions. S. aureus protection in the presence of exogenous alginate is due to the transcriptional downregulation of pvdA, a gene required for the production of the iron-scavenging siderophore pyoverdine as well as the downregulation of the PQS (Pseudomonas quinolone signal) (2-heptyl-3,4-dihydroxyquinoline) quorum sensing system. The impact of exogenous alginate is independent of endogenous alginate production. We further demonstrate that coculture of mucoid P. aeruginosa with nonmucoid P. aeruginosa strains can mitigate the killing of S. aureus by the nonmucoid strain of P. aeruginosa, indicating that the mechanism that we describe here may function in vivo in the context of mixed infections. Finally, we investigated a panel of mucoid clinical isolates that retain the ability to kill S. aureus at late time points and show that each strain has a unique expression profile, indicating that mucoid isolates can overcome the S. aureus-protective effects of mucoidy in a strain-specific manner. IMPORTANCE CF patients are chronically infected by polymicrobial communities. The two dominant bacterial pathogens that infect the lungs of CF patients are P. aeruginosa and S. aureus, with ∼30% of patients coinfected by both species. Such coinfected individuals have worse outcomes than monoinfected patients, and both species persist within the same physical space. A variety of host and environmental factors have been demonstrated to promote P. aeruginosa-S. aureus coexistence, despite evidence that P. aeruginosa kills S. aureus when these organisms are cocultured in vitro. Thus, a better understanding of P. aeruginosa-S. aureus interactions, particularly mechanisms by which these microorganisms are able to coexist in proximal physical space, will lead to better-informed treatments for chronic polymicrobial infections.

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Efficacy of Humanized Cefiderocol Exposures over 72 Hours against a Diverse Group of Gram-Negative Isolates in the Neutropenic Murine Thigh Infection Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01040-18 ◽

2018 ◽

Vol 63 (2) ◽

pp. e01040-18 ◽

Cited By ~ 3

Author(s):

Sean M. Stainton ◽

Marguerite L. Monogue ◽

Masakatsu Tsuji ◽

Yoshinori Yamano ◽

Roger Echols ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Acinetobacter Baumannii ◽

Infection Model ◽

Diverse Group ◽

Gram Negative ◽

Content Type ◽

Adaptive Resistance

ABSTRACT Herein, we evaluated sustainability of humanized exposures of cefiderocol in vivo over 72 h against pathogens with cefiderocol MICs of 0.5 to 16 μg/ml in the neutropenic murine thigh model. In Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae displaying MICs of 0.5 to 8 μg/ml (n = 11), sustained kill was observed at 72 h among 9 isolates. Postexposure MICs revealed a single 2-dilution increase in one animal compared with controls (1/54 samples, 1.8%) at 72 h. Adaptive resistance during therapy was not observed.

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Redesigning Escherichia coli Metabolism for Anaerobic Production of Isobutanol

Applied and Environmental Microbiology ◽

10.1128/aem.00382-11 ◽

2011 ◽

Vol 77 (14) ◽

pp. 4894-4904 ◽

Cited By ~ 79

Author(s):

Cong T. Trinh ◽

Johnny Li ◽

Harvey W. Blanch ◽

Douglas S. Clark

Keyword(s):

Escherichia Coli ◽

Anaerobic Growth ◽

Mode Analysis ◽

Glycolytic Flux ◽

Strictly Anaerobic ◽

Anaerobic Conditions ◽

Content Type ◽

E Coli ◽

Model Predictions ◽

Chromosomal Genes

ABSTRACTFermentation enables the production of reduced metabolites, such as the biofuels ethanol and butanol, from fermentable sugars. This work demonstrates a general approach for designing and constructing a production host that uses a heterologous pathway as an obligately fermentative pathway to produce reduced metabolites, specifically, the biofuel isobutanol. Elementary mode analysis was applied to design anEscherichia colistrain optimized for isobutanol production under strictly anaerobic conditions. The central metabolism ofE. coliwas decomposed into 38,219 functional, unique, and elementary modes (EMs). The model predictions revealed that during anaerobic growthE. colicannot produce isobutanol as the sole fermentative product. By deleting 7 chromosomal genes, the total 38,219 EMs were constrained to 12 EMs, 6 of which can produce high yields of isobutanol in a range from 0.29 to 0.41 g isobutanol/g glucose under anaerobic conditions. The remaining 6 EMs rely primarily on the pyruvate dehydrogenase enzyme complex (PDHC) and are typically inhibited under anaerobic conditions. The redesignedE. colistrain was constrained to employ the anaerobic isobutanol pathways through deletion of 7 chromosomal genes, addition of 2 heterologous genes, and overexpression of 5 genes. Here we present the design, construction, and characterization of an isobutanol-producingE. colistrain to illustrate the approach. The model predictions are evaluated in relation to experimental data and strategies proposed to improve anaerobic isobutanol production. We also show that the endogenous alcohol/aldehyde dehydrogenase AdhE is the key enzyme responsible for the production of isobutanol and ethanol under anaerobic conditions. The glycolytic flux can be controlled to regulate the ratio of isobutanol to ethanol production.

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The Anaerobic Regulatory Network Required for Pseudomonas aeruginosa Nitrate Respiration

Journal of Bacteriology ◽

10.1128/jb.00240-07 ◽

2007 ◽

Vol 189 (11) ◽

pp. 4310-4314 ◽

Cited By ~ 104

Author(s):

Kerstin Schreiber ◽

Robert Krieger ◽

Beatrice Benkert ◽

Martin Eschbach ◽

Hiroyuki Arai ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Dna Bending ◽

Regulatory Gene ◽

Regulatory System ◽

Growth Conditions ◽

Anaerobic Growth ◽

Nitrate Respiration ◽

Genetic Response ◽

Anaerobic Conditions ◽

Regulatory Model

ABSTRACT In Pseudomonas aeruginosa, the narK 1 K 2 GHJI operon encodes two nitrate/nitrite transporters and the dissimilatory nitrate reductase. The narK 1 promoter is anaerobically induced in the presence of nitrate by the dual activity of the oxygen regulator Anr and the N-oxide regulator Dnr in cooperation with the nitrate-responsive two-component regulatory system NarXL. The DNA bending protein IHF is essential for this process. Similarly, narXL gene transcription is enhanced under anaerobic conditions by Anr and Dnr. Furthermore, Anr and NarXL induce expression of the N-oxide regulator gene dnr. Finally, NarXL in cooperation with Dnr is required for anaerobic nitrite reductase regulatory gene nirQ transcription. A cascade regulatory model for the fine-tuned genetic response of P. aeruginosa to anaerobic growth conditions in the presence of nitrate was deduced.

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Disruption of Cross-Feeding Inhibits Pathogen Growth in the Sputa of Patients with Cystic Fibrosis

mSphere ◽

10.1128/msphere.00343-20 ◽

2020 ◽

Vol 5 (2) ◽

Cited By ~ 5

Author(s):

Jeffrey M. Flynn ◽

Lydia C. Cameron ◽

Talia D. Wiggen ◽

Jordan M. Dunitz ◽

William R. Harcombe ◽

...

Keyword(s):

Cystic Fibrosis ◽

Pseudomonas Aeruginosa ◽

Antibiotic Susceptibility ◽

Susceptibility Testing ◽

Anaerobic Bacteria ◽

Content Type ◽

Growth Environment ◽

Polymicrobial Infections

ABSTRACT A critical limitation in the management of chronic polymicrobial infections is the lack of correlation between antibiotic susceptibility testing (AST) and patient responses to therapy. Underlying this disconnect is our inability to accurately recapitulate the in vivo environment and complex polymicrobial communities in vitro. However, emerging evidence suggests that, if modeled and tested accurately, interspecies relationships can be exploited by conventional antibiotics predicted to be ineffective by standard AST. As an example, under conditions where Pseudomonas aeruginosa relies on cocolonizing organisms for nutrients (i.e., cross-feeding), multidrug-resistant P. aeruginosa may be indirectly targeted by inhibiting the growth of its metabolic partners. While this has been shown in vitro using synthetic bacterial communities, the efficacy of a “weakest-link” approach to controlling host-associated polymicrobial infections has not yet been demonstrated. To test whether cross-feeding inhibition can be leveraged in clinically relevant contexts, we collected sputa from cystic fibrosis (CF) subjects and used enrichment culturing to isolate both P. aeruginosa and anaerobic bacteria from each sample. Predictably, both subpopulations showed various antibiotic susceptibilities when grown independently. However, when P. aeruginosa was cultured and treated under cooperative conditions in which it was dependent on anaerobic bacteria for nutrients, the growth of both the pathogen and the anaerobe was constrained despite their intrinsic antibiotic resistance profiles. These data demonstrate that the control of complex polymicrobial infections may be achieved by exploiting obligate or facultative interspecies relationships. Toward this end, in vitro susceptibility testing should evolve to more accurately reflect in vivo growth environments and microbial interactions found within them. IMPORTANCE Antibiotic efficacy achieved in vitro correlates poorly with clinical outcomes after treatment of chronic polymicrobial diseases; if a pathogen demonstrates susceptibility to a given antibiotic in the lab, that compound is often ineffective when administered clinically. Conversely, if a pathogen is resistant in vitro, patient treatment with that same compound can elicit a positive response. This discordance suggests that the in vivo growth environment impacts pathogen antibiotic susceptibility. Indeed, here we demonstrate that interspecies relationships among microbiotas in the sputa of cystic fibrosis patients can be targeted to indirectly inhibit the growth of Pseudomonas aeruginosa. The therapeutic implication is that control of chronic lung infections may be achieved by exploiting obligate or facultative relationships among airway bacterial community members. This strategy is particularly relevant for pathogens harboring intrinsic multidrug resistance and is broadly applicable to chronic polymicrobial airway, wound, and intra-abdominal infections.

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Pseudomonas aeruginosa Regulatory Protein AnvM Controls Pathogenicity in Anaerobic Environments and Impacts Host Defense

mBio ◽

10.1128/mbio.01362-19 ◽

2019 ◽

Vol 10 (4) ◽

Cited By ~ 5

Author(s):

Yingchao Zhang ◽

Chuan-min Zhou ◽

Qinqin Pu ◽

Qun Wu ◽

Shirui Tan ◽

...

Keyword(s):

Oxidative Stress ◽

Immune Response ◽

Pseudomonas Aeruginosa ◽

Quorum Sensing ◽

Anaerobic Conditions ◽

Content Type ◽

Sensing System ◽

Quorum Sensing System ◽

Aerobic And Anaerobic ◽

Aerobic And Anaerobic Conditions

ABSTRACT Pseudomonas aeruginosa, one of the most common pathogens in hospital-acquired infections, is tightly controlled by a multilayered regulatory network, including the quorum sensing system (QS), the type VI secretion system (T6SS), and resistance to host immunity. We found that the P. aeruginosa 3880 (PA3880) gene, which encodes an unknown protein, acts as a regulator of anaerobic metabolism in response to oxidative stress and virulence in P. aeruginosa. More than 30 PA3880 homologs were found in other bacterial genomes, indicating that PA3880 is widely distributed in the Bacteria kingdom as a highly conserved gene. Deletion of the PA3880 gene changed the expression levels of more than 700 genes, including a group of virulence genes, under both aerobic and anaerobic conditions. To further study the mechanisms of PA3880-mediated regulation in virulence, we utilized a bacterial two-hybrid assay and found that the PA3880 protein interacted directly with QS regulator MvfR and anaerobic regulator Anr. Loss of the PA3880 protein significantly blunted the pathogenicity of P. aeruginosa, resulting in increased host survival, decreased bacterial burdens, reduced inflammatory responses, and fewer lung injuries in challenged mice hosts. Mechanistically, we found that Cys44 was a critical site for the full function of PA3880 in influencing alveolar macrophage phagocytosis and bacterial clearance. We also found that AnvM directly interacted with host receptors Toll-like receptor 2 (TLR2) and TLR5, which might lead to activation of the host immune response. Hence, we gave the name AnvM (anaerobic and virulence modulator) to the PA3880 protein. This characterization of AnvM could help to uncover new targets and strategies to treat P. aeruginosa infections. IMPORTANCE Infections by Pseudomonas aeruginosa, one of the most frequently isolated human pathogens, can create huge financial burdens. However, knowledge of the molecular mechanisms involved in the pathogenesis of P. aeruginosa remains elusive. We identified AnvM as a novel regulator of virulence in P. aeruginosa. Deletion of anvM altered the expression levels of more than 700 genes under aerobic and anaerobic conditions, including quorum sensing system genes and oxidative stress resistance genes. AnvM directly interacted with MvfR and Anr, thus regulating their downstream genes. More importantly, AnvM directly bound to TLR2 and TLR5, which turn on the host immune response. These findings provide insights into the significance of AnvM homologs in pathogenic bacteria and suggest a potential drug target against bacterial infection.

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Challenging Antimicrobial Susceptibility and Evolution of Resistance (OXA-681) during Treatment of a Long-Term Nosocomial Infection Caused by a Pseudomonas aeruginosa ST175 Clone

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01110-19 ◽

2019 ◽

Vol 63 (10) ◽

Cited By ~ 7

Author(s):

Jorge Arca-Suárez ◽

Pablo Fraile-Ribot ◽

Juan Carlos Vázquez-Ucha ◽

Gabriel Cabot ◽

Marta Martínez-Guitián ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Nosocomial Infection ◽

Resistance Mechanisms ◽

Cross Resistance ◽

The Novel ◽

Content Type ◽

Narrow Spectrum ◽

Extended Spectrum

ABSTRACT Selection of extended-spectrum mutations in narrow-spectrum oxacillinases (e.g., OXA-2 and OXA-10) is an emerging mechanism for development of in vivo resistance to ceftolozane-tazobactam and ceftazidime-avibactam in Pseudomonas aeruginosa. Detection of these challenging enzymes therefore seems essential to prevent clinical failure, but the complex phenotypic plasticity exhibited by this species may often lead to their underestimation. The underlying resistance mechanisms of two sequence type 175 (ST175) P. aeruginosa isolates showing multidrug-resistant phenotypes and recovered at early and late stages of a long-term nosocomial infection were evaluated. Whole-genome sequencing (WGS) was used to investigate resistance genomics, whereas molecular and biochemical methods were used for characterization of a novel extended-spectrum OXA-2 variant selected during therapy. The metallo-β-lactamase blaVIM-20 and the narrow-spectrum oxacillinase blaOXA-2 were present in both isolates, although they differed by an inactivating mutation in the mexB subunit, present only in the early isolate, and in a mutation in the blaOXA-2 β-lactamase, present only in the final isolate. The new OXA-2 variant, designated OXA-681, conferred elevated MICs of the novel cephalosporin–β-lactamase inhibitor combinations in a PAO1 background. Compared to OXA-2, kinetic parameters of the OXA-681 enzyme revealed a substantial increase in the hydrolysis of cephalosporins, including ceftolozane. We describe the emergence of the novel variant OXA-681 during treatment of a nosocomial infection caused by a Pseudomonas aeruginosa ST175 high-risk clone. The ability of OXA-681 to confer cross-resistance to ceftolozane-tazobactam and ceftazidime-avibactam together with the complex antimicrobial resistance profiles exhibited by the clinical strains harboring this new enzyme argue for maintaining active surveillance on emerging broad-spectrum resistance in P. aeruginosa.

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In Vivo Fitness Adaptations of Colistin-Resistant Acinetobacter baumannii Isolates to Oxidative Stress

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00598-16 ◽

2016 ◽

Vol 61 (3) ◽

Cited By ~ 8

Author(s):

Crystal L. Jones ◽

Shweta S. Singh ◽

Yonas Alamneh ◽

Leila G. Casella ◽

Robert K. Ernst ◽

...

Keyword(s):

Oxidative Stress ◽

Hydrogen Peroxide ◽

Acinetobacter Baumannii ◽

Catalase Activity ◽

Content Type ◽

Increased Susceptibility

ABSTRACT The loss of fitness in colistin-resistant (CR) Acinetobacter baumannii was investigated using longitudinal isolates from the same patient. Early CR isolates were outcompeted by late CR isolates for growth in broth and survival in the lungs of mice. Fitness loss was associated with an increased susceptibility to oxidative stress since early CR strains had reduced in vitro survival in the presence of hydrogen peroxide and decreased catalase activity compared to that of late CR and colistin-susceptible (CS) strains.

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