Publications by authors named "Fabrice Biot"

17 Publications

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Lessons learned from the investigation of a COVID-19 cluster in Creil, France: effectiveness of targeting symptomatic cases and conducting contact tracing around them.

BMC Infect Dis 2021 May 19;21(1):457. Epub 2021 May 19.

SSA (French Military Health Service), Bégin Military Teaching Hospital, Saint-Mandé, France.

Background: This study presents the methods and results of the investigation into a SARS-CoV-2 outbreak in a professional community. Due to the limited testing capacity available in France at the time, we elaborated a testing strategy according to pre-test probability.

Methods: The investigation design combined active case finding and contact tracing around each confirmed case with testing of at-risk contact persons who had any evocative symptoms (n = 88). One month later, we performed serology testing to test and screen symptomatic and asymptomatic cases again (n = 79).

Results: Twenty-four patients were confirmed (14 with RT-PCR and 10 with serology). The attack rate was 29% (24/83). Median age was 40 (24 to 59), and the sex ratio was 15/12. Only three cases were asymptomatic (= no symptoms at all, 13%, 95% CI, 3-32). Nineteen symptomatic cases (79%, 95% CI, 63-95) presented a respiratory infection, two of which were severe. All the RT-PCR confirmed cases acquired protective antibodies. Median incubation was 4 days (from 1 to 13 days), and the median serial interval was 3 days (0 to 15). We identified pre-symptomatic transmission in 40% of this cluster, but no transmission from asymptomatic to symptomatic cases.

Conclusion: We report the effective use of targeted testing according to pre-test probability, specifically prioritizing symptomatic COVID-19 diagnosis and contact tracing. The asymptomatic rate raises questions about the real role of asymptomatic infected people in transmission. Conversely, pre-symptomatic contamination occurred frequently in this cluster, highlighting the need to identify, test, and quarantine asymptomatic at-risk contact persons (= contact tracing). The local lockdown imposed helped reduce transmission during the investigation period.
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http://dx.doi.org/10.1186/s12879-021-06166-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8133048PMC
May 2021

Genomic and RT-qPCR analysis of trimethoprim-sulfamethoxazole and meropenem resistance in Burkholderia pseudomallei clinical isolates.

PLoS Negl Trop Dis 2021 02 16;15(2):e0008913. Epub 2021 Feb 16.

Bacteriology Unit, UMR-MD1 INSERM 1261, French Armed Biomedical Research Institut, Brétigny-sur-Orge, France.

Background: Melioidosis is an endemic disease in southeast Asia and northern Australia caused by the saprophytic bacteria Burkholderia pseudomallei, with a high mortality rate. The clinical presentation is multifaceted, with symptoms ranging from acute septicemia to multiple chronic abscesses. Here, we report a chronic case of melioidosis in a patient who lived in Malaysia in the 70s and was suspected of contracting tuberculosis. Approximately 40 years later, in 2014, he was diagnosed with pauci-symptomatic melioidosis during a routine examination. Four strains were isolated from a single sample. They showed divergent morphotypes and divergent antibiotic susceptibility, with some strains showing resistance to trimethoprim-sulfamethoxazole and fluoroquinolones. In 2016, clinical samples were still positive for B. pseudomallei, and only one type of strain, showing atypical resistance to meropenem, was isolated.

Principal Findings: We performed whole genome sequencing and RT-qPCR analysis on the strains isolated during this study to gain further insights into their differences. We thus identified two types of resistance mechanisms in these clinical strains. The first one was an adaptive and transient mechanism that disappeared during the course of laboratory sub-cultures; the second was a mutation in the efflux pump regulator amrR, associated with the overexpression of the related transporter.

Conclusion: The development of such mechanisms may have a clinical impact on antibiotic treatment. Indeed, their transient nature could lead to an undiagnosed resistance. Efflux overexpression due to mutation leads to an important multiple resistance, reducing the effectiveness of antibiotics during treatment.
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http://dx.doi.org/10.1371/journal.pntd.0008913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909661PMC
February 2021

Evolution of Antibiotic Resistance in Surrogates of (LVS and ): Effects on Biofilm Formation and Fitness.

Front Microbiol 2020 30;11:593542. Epub 2020 Oct 30.

Bacteriology Division, U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), Frederick, MD, United States.

, the causative agent of tularemia, is capable of causing disease in a multitude of mammals and remains a formidable human pathogen due to a high morbidity, low infectious dose, lack of a FDA approved vaccine, and ease of aerosolization. For these reasons, there is concern over the use of as a biological weapon, and, therefore, it has been classified as a Tier 1 select agent. Fluoroquinolones and aminoglycosides often serve as the first line of defense for treatment of tularemia. However, high levels of resistance to these antibiotics has been observed in gram-negative bacteria in recent years, and naturally derived resistant strains have been described in the literature. The acquisition of antibiotic resistance, either natural or engineered, presents a challenge for the development of medical countermeasures. In this study, we generated a surrogate panel of antibiotic resistant and Live Vaccine Strain (LVS) by selection in the presence of antibiotics and characterized their growth, biofilm capacity, and fitness. These experiments were carried out in an effort to (1) assess the fitness of resistant strains; and (2) identify new targets to investigate for the development of vaccines or therapeutics. All strains exhibited a high level of resistance to either ciprofloxacin or streptomycin, a fluoroquinolone and aminoglycoside, respectively. Whole genome sequencing of this panel revealed both on-pathway and off-pathway mutations, with more mutations arising in LVS. For , we observed decreased biofilm formation for all ciprofloxacin resistant strains compared to wild-type, while streptomycin resistant isolates were unaffected in biofilm capacity. The fitness of representative antibiotic resistant strains was assessed in murine macrophage-like cell lines, and also in a murine model of pneumonic infection. These experiments revealed that mutations obtained by these methods led to nearly all ciprofloxacin resistant strains tested being completely attenuated while mild attenuation was observed in streptomycin resistant strains. This study is one of the few to examine the link between acquired antibiotic resistance and fitness in spp., as well as enable the discovery of new targets for medical countermeasure development.
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http://dx.doi.org/10.3389/fmicb.2020.593542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661474PMC
October 2020

Natural outbreaks and bioterrorism: How to deal with the two sides of the same coin?

J Glob Health 2020 Dec;10(2):020317

Bacteriology Unit, French Armed Forces Biomedical Research Institute (IRBA), Bretigny sur Orge, France.

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http://dx.doi.org/10.7189/jogh.10.020317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7535343PMC
December 2020

Modeling the Inactivation of Viruses from the Family in Response to Temperature and Relative Humidity in Suspensions or on Surfaces.

Appl Environ Microbiol 2020 09 1;86(18). Epub 2020 Sep 1.

Risk Assessment Department, French Agency for Food, Environmental and Occupational Health and Safety, Maisons-Alfort, France.

Temperature and relative humidity are major factors determining virus inactivation in the environment. This article reviews inactivation data regarding coronaviruses on surfaces and in liquids from published studies and develops secondary models to predict coronaviruses inactivation as a function of temperature and relative humidity. A total of 102 values (i.e., the time to obtain a log reduction of virus infectivity), including values for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), were collected from 26 published studies. The values obtained from the different coronaviruses and studies were found to be generally consistent. Five different models were fitted to the global data set of values. The most appropriate model considered temperature and relative humidity. A spreadsheet predicting the inactivation of coronaviruses and the associated uncertainty is presented and can be used to predict virus inactivation for untested temperatures, time points, or any coronavirus strains belonging to and genera. The prediction of the persistence of SARS-CoV-2 on fomites is essential in investigating the importance of contact transmission. This study collects available information on inactivation kinetics of coronaviruses in both solid and liquid fomites and creates a mathematical model for the impact of temperature and relative humidity on virus persistence. The predictions of the model can support more robust decision-making and could be useful in various public health contexts. A calculator for the natural clearance of SARS-CoV-2 depending on temperature and relative humidity could be a valuable operational tool for public authorities.
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http://dx.doi.org/10.1128/AEM.01244-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480392PMC
September 2020

Case Report of an Injectional Anthrax in France, 2012.

Microorganisms 2020 Jun 30;8(7). Epub 2020 Jun 30.

CNR-LE Charbon (National Reference Laboratory for Anthrax), Institut de Recherche Biomédicale des Armées, 1 Place Général Valérie André, 91220 Brétigny sur Orge, France.

(1) Background: is a spore-forming, Gram-positive bacterium causing anthrax, a zoonosis affecting mainly livestock. When occasionally infecting humans, provokes three different clinical forms: cutaneous, digestive and inhalational anthrax. More recently, an injectional anthrax form has been described in intravenous drug users. (2) Case presentation: We report here the clinical and microbiological features, as well as the strain phylogenetic analysis, of the only injectional anthrax case observed in France so far. A 27-year-old patient presented a massive dermohypodermatitis with an extensive edema of the right arm, and the development of drug-resistant shocks. After three weeks in an intensive care unit, the patient recovered, but the microbiological identification of was achieved after a long delay. (3) Conclusions: Anthrax diagnostic may be difficult clinically and microbiologically. The phylogenetic analysis of the strain PF1 confirmed its relatedness to the injectional anthrax European outbreak group-II.
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http://dx.doi.org/10.3390/microorganisms8070985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409126PMC
June 2020

Nutrient depletion may trigger the Yersinia pestis OmpR-EnvZ regulatory system to promote flea-borne plague transmission.

Mol Microbiol 2019 11 13;112(5):1471-1482. Epub 2019 Sep 13.

University of Lille, INSERM, CNRS, CHU Lille, Institut Pasteur de Lille, U1019-UMR8204, CIIL-Center for Infection and Immunity of Lille, F-59000, Lille, France.

The flea's lumen gut is a poorly documented environment where the agent of flea-borne plague, Yersinia pestis, must replicate to produce a transmissible infection. Here, we report that both the acidic pH and osmolarity of the lumen's contents display simple harmonic oscillations with different periods. Since an acidic pH and osmolarity are two of three known stimuli of the OmpR-EnvZ two-component system in bacteria, we investigated the role and function of this Y. pestis system in fleas. By monitoring the in vivo expression pattern of three OmpR-EnvZ-regulated genes, we concluded that the flea gut environment triggers OmpR-EnvZ. This activation was not, however, correlated with changes in pH and osmolarity but matched the pattern of nutrient depletion (the third known stimulus for OmpR-EnvZ). Lastly, we found that the OmpR-EnvZ and the OmpF porin are needed to produce the biofilm that ultimately obstructs the flea's gut and thus hastens the flea-borne transmission of plague. Taken as a whole, our data suggest that the flea gut is a complex, fluctuating environment in which Y. pestis senses nutrient depletion via OmpR-EnvZ. Once activated, the latter triggers a molecular program (including at least OmpF) that produces the biofilm required for efficient plague transmission.
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http://dx.doi.org/10.1111/mmi.14372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842400PMC
November 2019

A Mutant, Lacking the Soluble Lytic Transglycosylase Slt, Exhibits Defects in Both Growth and Virulence.

Front Microbiol 2019 14;10:1343. Epub 2019 Jun 14.

Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Frederick, MD, United States.

is the causative agent of tularemia and has gained recent interest as it poses a significant biothreat risk. is commonly used as a laboratory surrogate for tularemia research due to genetic similarity and susceptibility of mice to infection. Currently, there is no FDA-approved tularemia vaccine, and identifying therapeutic targets remains a critical gap in strategies for combating this pathogen. Here, we investigate the soluble lytic transglycosylase or Slt in , which belongs to a class of peptidoglycan-modifying enzymes known to be involved in cell division. We assess the role of Slt in biology and virulence of the organism as well as the vaccine potential of the mutant. We show that the mutant has a significant growth defect in acidic pH conditions. Further microscopic analysis revealed significantly altered cell morphology compared to wild-type, including larger cell size, extensive membrane protrusions, and cell clumping and fusion, which was partially restored by growth in neutral pH or genetic complementation. Viability of the mutant was also significantly decreased during growth in acidic medium, but not at neutral pH. Furthermore, the mutant exhibited significant attenuation in a murine model of intranasal infection and virulence could be restored by genetic complementation. Moreover, we could protect mice using the mutant as a live vaccine strain against challenge with the parent strain; however, we were not able to protect against challenge with the fully virulent Schu S4 strain. These studies demonstrate a critical role for the Slt enzyme in maintaining proper cell division and morphology in acidic conditions, as well as replication and virulence . Our results suggest that although the current vaccination strategy with mutant would not protect against Schu S4 challenges, the Slt enzyme could be an ideal target for future therapeutic development.
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http://dx.doi.org/10.3389/fmicb.2019.01343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587636PMC
June 2019

Questionable Efficacy of Therapeutic Antibodies in the Treatment of Anthrax.

mSphere 2019 06 19;4(3). Epub 2019 Jun 19.

Institut de Recherche Biomédicale des Armées, Bacteriology, Anti-infectious Biotherapies, and Immunity Unit, Brétigny-sur-Orge, France.

Inhalational anthrax caused by , a spore-forming Gram-positive bacterium, is a highly lethal infection. Antibodies targeting the protective antigen (PA) binding component of the toxins have recently been authorized as an adjunct to antibiotics, although no conclusive evidence demonstrates that anthrax antitoxin therapy has any significant benefit. We discuss here the rational basis of anti-PA development regarding the pathogenesis of the disease. We argue that inductive reasoning may induce therapeutic bias. We identified anthrax animal model analysis as another bias. Further studies are needed to assess the benefit of anti-PA antibodies in the treatment of inhalational anthrax, while a clearer consensus should be established around what evidence should be proven in an anthrax model.
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http://dx.doi.org/10.1128/mSphere.00282-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584371PMC
June 2019

Transcriptomic studies and assessment of Yersinia pestis reference genes in various conditions.

Sci Rep 2019 02 21;9(1):2501. Epub 2019 Feb 21.

Institut de Recherche Biomédicale des Armées (IRBA), Brétigny-sur-Orge, France.

Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) is a very sensitive widespread technique considered as the gold standard to explore transcriptional variations. While a particular methodology has to be followed to provide accurate results many published studies are likely to misinterpret results due to lack of minimal quality requirements. Yersinia pestis is a highly pathogenic bacterium responsible for plague. It has been used to propose a ready-to-use and complete approach to mitigate the risk of technical biases in transcriptomic studies. The selection of suitable reference genes (RGs) among 29 candidates was performed using four different methods (GeNorm, NormFinder, BestKeeper and the Delta-Ct method). An overall comprehensive ranking revealed that 12 following candidate RGs are suitable for accurate normalization: gmk, proC, fabD, rpoD, nadB, rho, thrA, ribD, mutL, rpoB, adk and tmk. Some frequently used genes like 16S RNA had even been found as unsuitable to study Y. pestis. This methodology allowed us to demonstrate, under different temperatures and states of growth, significant transcriptional changes of six efflux pumps genes involved in physiological aspects as antimicrobial resistance or virulence. Previous transcriptomic studies done under comparable conditions had not been able to highlight these transcriptional modifications. These results highlight the importance of validating RGs prior to the normalization of transcriptional expression levels of targeted genes. This accurate methodology can be extended to any gene of interest in Y. pestis. More generally, the same workflow can be applied to identify and validate appropriate RGs in other bacteria to study transcriptional variations.
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http://dx.doi.org/10.1038/s41598-019-39072-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6385181PMC
February 2019

The threat of bioterrorism.

Lancet Infect Dis 2019 01;19(1):18-19

Infectious Diseases Department, Hôpital d'Instruction des Armées Laveran, Marseille, France.

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http://dx.doi.org/10.1016/S1473-3099(18)30709-6DOI Listing
January 2019

Melioidosis in the Western Indian Ocean and the Importance of Improving Diagnosis, Surveillance, and Molecular Typing.

Trop Med Infect Dis 2018 Mar 7;3(1). Epub 2018 Mar 7.

Unité de Bactériologie Expérimentale, Institut Pasteur de Madagascar, Antananarivo 101, Madagascar.

Melioidosis, caused by the bacterium , is an infectious disease of humans or animals, and the specific environmental conditions that are present in western Indian Ocean islands are particularly suitable for the establishment/survival of . Indeed, an increasing number of new cases have been reported in this region (Madagascar, Mauritius, Réunion (France), and Seychelles, except Comoros and Mayotte (France)), and are described in this review. Our review clearly points out that further studies are needed in order to investigate the real incidence and burden of melioidosis in the western Indian Ocean and especially Madagascar, since it is likely to be higher than currently reported. Thus, research and surveillance priorities were recommended (i) to improve awareness of melioidosis in the population and among clinicians; (ii) to improve diagnostics, in order to provide rapid and effective treatment; (iii) to implement a surveillance and reporting system in the western Indian Ocean; and (iv) to investigate the presence of in environmental samples, since we have demonstrated its presence in soil samples originating from the yard of a Madagascan case.
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http://dx.doi.org/10.3390/tropicalmed3010030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136609PMC
March 2018

A spontaneous mutation in kdsD, a biosynthesis gene for 3 Deoxy-D-manno-Octulosonic Acid, occurred in a ciprofloxacin resistant strain of Francisella tularensis and caused a high level of attenuation in murine models of tularemia.

PLoS One 2017 22;12(3):e0174106. Epub 2017 Mar 22.

Bacteriology Division, USAMRIID, Fort Detrick, Frederick, MD, United States of America.

Francisella tularensis, a gram-negative facultative intracellular bacterial pathogen, is the causative agent of tularemia and able to infect many mammalian species, including humans. Because of its ability to cause a lethal infection, low infectious dose, and aerosolizable nature, F. tularensis subspecies tularensis is considered a potential biowarfare agent. Due to its in vitro efficacy, ciprofloxacin is one of the antibiotics recommended for post-exposure prophylaxis of tularemia. In order to identify therapeutics that will be efficacious against infections caused by drug resistant select-agents and to better understand the threat, we sought to characterize an existing ciprofloxacin resistant (CipR) mutant in the Schu S4 strain of F. tularensis by determining its phenotypic characteristics and sequencing the chromosome to identify additional genetic alterations that may have occurred during the selection process. In addition to the previously described genetic alterations, the sequence of the CipR mutant strain revealed several additional mutations. Of particular interest was a frameshift mutation within kdsD which encodes for an enzyme necessary for the production of 3-Deoxy-D-manno-Octulosonic Acid (KDO), an integral component of the lipopolysaccharide (LPS). A kdsD mutant was constructed in the Schu S4 strain. Although it was not resistant to ciprofloxacin, the kdsD mutant shared many phenotypic characteristics with the CipR mutant, including growth defects under different conditions, sensitivity to hydrophobic agents, altered LPS profiles, and attenuation in multiple models of murine tularemia. This study demonstrates that the KdsD enzyme is essential for Francisella virulence and may be an attractive therapeutic target for developing novel medical countermeasures.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0174106PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5362203PMC
August 2017

Interplay between three RND efflux pumps in doxycycline-selected strains of Burkholderia thailandensis.

PLoS One 2013 27;8(12):e84068. Epub 2013 Dec 27.

Unité de Bactériologie/UMR_MD 1, Institut de Recherche Biomédicale des Armées, Brétigny-sur-Orge, France ; UMR_MD 1, Aix Marseille Université, IRBA, Facultés de Médecine et de Pharmacie, Marseille, France ; Ecole du Val-de-Grâce, Paris, France.

Background: Efflux systems are involved in multidrug resistance in most Gram-negative non-fermentative bacteria. We have chosen Burkholderia thailandensis to dissect the development of multidrug resistance phenotypes under antibiotic pressure.

Methodology/principal Findings: We used doxycycline selection to obtain several resistant B. thailandensis variants. The minimal inhibitory concentrations of a large panel of structurally unrelated antibiotics were determined ± the efflux pump inhibitor phenylalanine-arginine ß-naphthylamide (PAßN). Membrane proteins were identified by proteomic method and the expressions of major efflux pumps in the doxycycline selected variants were compared to those of the parental strains by a quantitative RT-PCR analysis. Doxycycline selected variants showed a multidrug resistance in two major levels corresponding to the overproduction of two efflux pumps depending on its concentration: AmrAB-OprA and BpeEF-OprC. The study of two mutants, each lacking one of these pumps, indicated that a third pump, BpeAB-OprB, could substitute for the defective pump. Surprisingly, we observed antagonistic effects between PAßN and aminoglycosides or some ß-lactams. PAßN induced the overexpression of AmrAB-OprA and BpeAB-OprB pump genes, generating this unexpected effect.

Conclusions/significance: These results may account for the weak activity of PAßN in some Gram-negative species. We clearly demonstrated two antagonistic effects of this molecule on bacterial cells: the blocking of antibiotic efflux and an increase in efflux pump gene expression. Thus, doxycycline is a very efficient RND efflux pump inducer and PAßN may promote the production of some efflux pumps. These results should be taken into account when considering antibiotic treatments and in future studies on efflux pump inhibitors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0084068PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3873969PMC
August 2014

Growth inhibition of pathogenic bacteria by sulfonylurea herbicides.

Antimicrob Agents Chemother 2013 Mar 21;57(3):1513-7. Epub 2012 Dec 21.

Genome Institute of Singapore, Singapore.

Emerging resistance to current antibiotics raises the need for new microbial drug targets. We show that targeting branched-chain amino acid (BCAA) biosynthesis using sulfonylurea herbicides, which inhibit the BCAA biosynthetic enzyme acetohydroxyacid synthase (AHAS), can exert bacteriostatic effects on several pathogenic bacteria, including Burkholderia pseudomallei, Pseudomonas aeruginosa, and Acinetobacter baumannii. Our results suggest that targeting biosynthetic enzymes like AHAS, which are lacking in humans, could represent a promising antimicrobial drug strategy.
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http://dx.doi.org/10.1128/AAC.02327-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3591922PMC
March 2013

Involvement of the efflux pumps in chloramphenicol selected strains of Burkholderia thailandensis: proteomic and mechanistic evidence.

PLoS One 2011 Feb 9;6(2):e16892. Epub 2011 Feb 9.

UMR-MD-1, Facultés de Médecine et de Pharmacie, Université de la Méditerranée, IFR88, Marseille, France.

Burkholderia is a bacterial genus comprising several pathogenic species, including two species highly pathogenic for humans, B. pseudomallei and B. mallei. B. thailandensis is a weakly pathogenic species closely related to both B. pseudomallei and B. mallei. It is used as a study model. These bacteria are able to exhibit multiple resistance mechanisms towards various families of antibiotics. By sequentially plating B. thailandensis wild type strains on chloramphenicol we obtained several resistant variants. This chloramphenicol-induced resistance was associated with resistance against structurally unrelated antibiotics including quinolones and tetracyclines. We functionally and proteomically demonstrate that this multidrug resistance phenotype, identified in chloramphenicol-resistant variants, is associated with the overexpression of two different efflux pumps. These efflux pumps are able to expel antibiotics from several families, including chloramphenicol, quinolones, tetracyclines, trimethoprim and some β-lactams, and present a partial susceptibility to efflux pump inhibitors. It is thus possible that Burkholderia species can develop such adaptive resistance mechanisms in response to antibiotic pressure resulting in emergence of multidrug resistant strains. Antibiotics known to easily induce overexpression of these efflux pumps should be used with discernment in the treatment of Burkholderia infections.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0016892PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3036723PMC
February 2011