Antibiotic resistance via bacterial cell shape-shifting

Bacteria have evolved to develop multiple strategies for antibiotic resistance by effectively reducing intracellular antibiotic concentrations or antibiotic binding affinities, but the role of cell morphology on antibiotic resistance remains poorly characterized. By analyzing cell morphological data of different bacterial species under antibiotic stress, we find that bacterial cells robustly reduce surface-to-volume ratio in response to most types of antibiotics. Using quantitative modelling we show that by reducing surface-to-volume ratio, bacteria can effectively reduce intracellular antibiotic concentration by decreasing antibiotic influx. The model predicts that bacteria can increase surface-to-volume ratio to promote antibiotic dilution if efflux pump activity is reduced, in agreement with data on membrane-transport inhibitors. Using the particular example of ribosome-targeting antibiotics, we present a systems-level model for the regulation of cell shape under antibiotic stress, and discuss feedback mechanisms that bacteria can harness to increase their fitness in the presence of antibiotics.

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Two resistance nodulation division-family efflux pumps inChromobacteriumspecies and their role in antibiotic resistance and tolerance

10.1101/562140 ◽

2019 ◽

Author(s):

Saida Benomar ◽

Kara C Evans ◽

Robert L Unckless ◽

Josephine R Chandler

Keyword(s):

Antibiotic Resistance ◽

Efflux Pump ◽

Bacterial Species ◽

Efflux Pumps ◽

Resistance Mechanisms ◽

Antibiotic Resistant ◽

Burkholderia Thailandensis ◽

New Information ◽

Resistance Nodulation Division ◽

Culture Growth

ABSTRACTVery little is known of the antibiotic resistance mechanisms of members of theChromobacteriumgenus. In previous studies ofChromobacterium subtsugae(formerlyC. violaceum) strain CV017, we identified a resistance nodulation division (RND)-family efflux pump (CdeAB-OprM). Here, we show thecdeAB-oprMgenes are widely distributed in members of theChromobacteriumgenus. We use antimicrobial susceptibility testing with a CV017cdeAB-oprMmutant to show the products of these genes confers resistance to a variety of antibiotics including ciprofloxacin, a clinically important antibiotic. We also identified a related RND-family pump,cseAB-oprN, in the genome of CV017 and otherC. subtsugaespecies, that is not present in other members of theChromobacteriumgenus. We demonstrate that CdeAB-OprM and CseAB-OprN are both transcriptionally induced in CV017 cells treated with sub-lethal antibiotic concentrations and they are important for induction of tolerance to different antibiotics. While CdeAB-OprM has a broad antibiotic specificity, the CseAB-OprN system is highly specific for a ribosome-targeting antibiotic produced by the saprophytic bacteriumBurkholderia thailandensis,bactobolin. Finally, we use a previously developedB. thailandensis-C. subtsugaeCV017 co-culture model to demonstrate that adding sub-lethal bactobolin at the beginning of co-culture growth increases the ability of CV017 to compete withB. thailandensisin a manner that is dependent on the CseAB-OprN system. Our results provide new information on the antibiotic resistance mechanisms ofChromobacteriumspecies and highlight the importance of efflux pumps during competition with other bacterial species.IMPORTANCEThis study describes two closely related efflux pumps in members of theChromobacteriumgenus, which includes opportunistic but often-fatal pathogens and species with highly versatile metabolic capabilities. Efflux pumps remove antibiotics from the cell and are important for antibiotic resistance. One of these pumps is broadly distributed in theChromobacteriumgenus and increases resistance to clinically relevant antibiotics. The other efflux pump is present only inChromobacterium subtsugaeand is highly specific for bactobolin, an antibiotic produced by the soil saprophyteBurkholderia thailandensis. We demonstrate these pumps can be activated to increase resistance by their antibiotic substrates, and that this activation is important forC. subtsugaeto survive in a laboratory competition experiment withB. thailandensis.These results have implications for managing antibiotic-resistantChromobacteriuminfections, bioengineering ofChromobacteriumspecies, and for understanding the evolution of efflux pumps.

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Antibiotic Resistance Can Be Enhanced in Gram-Positive Species by Some Biocidal Agents Used for Disinfection

Antibiotics ◽

10.3390/antibiotics8010013 ◽

2019 ◽

Vol 8 (1) ◽

pp. 13 ◽

Cited By ~ 11

Author(s):

Günter Kampf

Keyword(s):

Antibiotic Resistance ◽

Efflux Pump ◽

Bacterial Species ◽

Cross Resistance ◽

Pressure Potential ◽

Gram Positive ◽

Medline Search ◽

Didecyldimethylammonium Chloride ◽

Healthcare Associated ◽

Sublethal Concentrations

Some biocidal agents used for disinfection have been described to enhance antibiotic resistance in Gram-negative species. The aim of this review was therefore to evaluate the effect of 13 biocidal agents at sublethal concentrations on antibiotic resistance in Gram-positive species. A MEDLINE search was performed for each biocidal agent on antibiotic tolerance, antibiotic resistance, horizontal gene transfer, and efflux pump. Most data were reported with food-associated bacterial species. In cells adapted to benzalkonium chloride, a new resistance was most frequently found to ampicillin (seven species), cefotaxime and sulfamethoxazole (six species each), and ceftazidime (five species), some of them with relevance for healthcare-associated infections such as Enterococcus faecium and Enterococcus faecalis. With chlorhexidine, a new resistance was often found to imipenem (ten species) as well as cefotaxime, ceftazidime, and tetracycline (seven species each). Cross-resistance was also found with triclosan and ceftazidime (eight species), whereas it was very uncommon for didecyldimethylammonium chloride or hydrogen peroxide. No cross-resistance to antibiotics has been described after low level exposure to glutaraldehyde, ethanol, propanol, peracetic acid, octenidine, povidone iodine, sodium hypochlorite, and polyhexanide. Preference should be given to disinfectant formulations based on biocidal agents with a low or no selection pressure potential.

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Bacteriophage selection against a plasmid-encoded sex apparatus leads to the loss of antibiotic-resistance plasmids

Biology Letters ◽

10.1098/rsbl.2011.0384 ◽

2011 ◽

Vol 7 (6) ◽

pp. 902-905 ◽

Cited By ~ 41

Author(s):

Matti Jalasvuori ◽

Ville-Petri Friman ◽

Anne Nieminen ◽

Jaana K. H. Bamford ◽

Angus Buckling

Keyword(s):

Antibiotic Resistance ◽

Resistance Genes ◽

Bacterial Species ◽

Low Frequency ◽

Antibiotic Resistance Genes ◽

Resistant Bacteria ◽

Bacterial Cells ◽

Antibiotic Resistant ◽

Resistance Plasmids ◽

Resistant Mutants

Antibiotic-resistance genes are often carried by conjugative plasmids, which spread within and between bacterial species. It has long been recognized that some viruses of bacteria (bacteriophage; phage) have evolved to infect and kill plasmid-harbouring cells. This raises a question: can phages cause the loss of plasmid-associated antibiotic resistance by selecting for plasmid-free bacteria, or can bacteria or plasmids evolve resistance to phages in other ways? Here, we show that multiple antibiotic-resistance genes containing plasmids are stably maintained in both Escherichia coli and Salmonella enterica in the absence of phages, while plasmid-dependent phage PRD1 causes a dramatic reduction in the frequency of antibiotic-resistant bacteria. The loss of antibiotic resistance in cells initially harbouring RP4 plasmid was shown to result from evolution of phage resistance where bacterial cells expelled their plasmid (and hence the suitable receptor for phages). Phages also selected for a low frequency of plasmid-containing, phage-resistant bacteria, presumably as a result of modification of the plasmid-encoded receptor. However, these double-resistant mutants had a growth cost compared with phage-resistant but antibiotic-susceptible mutants and were unable to conjugate. These results suggest that bacteriophages could play a significant role in restricting the spread of plasmid-encoded antibiotic resistance.

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Expression ofPseudomonas aeruginosaAntibiotic Resistance Genes Varies Greatly during Infections in Cystic Fibrosis Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01789-18 ◽

2018 ◽

Vol 62 (11) ◽

Cited By ~ 8

Author(s):

Lois W. Martin ◽

Cynthia L. Robson ◽

Annabelle M. Watts ◽

Andrew R. Gray ◽

Claire E. Wainwright ◽

...

Keyword(s):

Gene Expression ◽

Cystic Fibrosis ◽

Antibiotic Resistance ◽

Efflux Pump ◽

Antibiotic Resistance Gene ◽

Resistance Mechanisms ◽

Laboratory Culture ◽

Bacterial Cells ◽

Content Type ◽

Key Factor

ABSTRACTThe lungs of individuals with cystic fibrosis (CF) become chronically infected withPseudomonas aeruginosathat is difficult to eradicate by antibiotic treatment. Two keyP. aeruginosaantibiotic resistance mechanisms are the AmpC β-lactamase that degrades β-lactam antibiotics and MexXYOprM, a three-protein efflux pump that expels aminoglycoside antibiotics from the bacterial cells. Levels of antibiotic resistance gene expression are likely to be a key factor in antibiotic resistance but have not been determined during infection. The aims of this research were to investigate the expression of theampCandmexXgenes during infection in patients with CF and in bacteria isolated from the same patients and grown under laboratory conditions.P. aeruginosaisolates from 36 CF patients were grown in laboratory culture and gene expression measured by reverse transcription-quantitative PCR (RT-qPCR). The expression ofampCvaried over 20,000-fold and that ofmexXover 2,000-fold between isolates. The median expression levels of both genes were increased by the presence of subinhibitory concentrations of antibiotics. To measureP. aeruginosagene expression during infection, we carried out RT-qPCR using RNA extracted from fresh sputum samples obtained from 31 patients. The expression ofampCvaried over 4,000-fold, whilemexXexpression varied over 100-fold, between patients. Despite these wide variations, median levels of expression ofampCin bacteria in sputum were similar to those in laboratory-grown bacteria. The expression ofmexXwas higher in sputum than in laboratory-grown bacteria. Overall, our data demonstrate that genes that contribute to antibiotic resistance can be highly expressed in patients, but there is extensive isolate-to-isolate and patient-to-patient variation.

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Mechanisms of Antibiotic Resistance

Tutorial Topics in Infection for the Combined Infection Training Programme ◽

10.1093/oso/9780198801740.003.0055 ◽

2019 ◽

Author(s):

Ruaridh Buchanan ◽

David Wareham

Keyword(s):

Antibiotic Resistance ◽

Dna Replication ◽

Selection Pressure ◽

Bacterial Species ◽

Resistance Mechanisms ◽

Drug Resistant ◽

Bacterial Cells ◽

Gram Negative ◽

The Times ◽

Gram Negative Organisms

Although antibiotic resistance has come to the fore in the media and clinical practice relatively recently, it is by no means a new issue; Alexander Fleming discussed the risks of penicillin resistance more than sixty years ago, but even he was behind the times. Bacteria have been competing with each other for millions of years, producing compounds which kill or inhibit other species—it is not surprising that bacteria have evolved defence mechanisms. Current major concerns are the rise of pan-drug resistant gram-negative organisms and the spread of multi-drug resistant TB. Bacterial cells turn over rapidly—this rate of reproduction leads to many errors in DNA replication. Many of these mutations are deleterious to the organism, but others confer new properties, such as changing the structure of an enzyme. The application of selection pressure in the form of antimicrobial therapy leads to the survival of mutants that have randomly acquired resistance mechanisms. There are two useful ways to categorize resistance mechanisms: by how bacterial cells acquire them and by the physical mechanism of action. The types of acquisition have important infection control ramifications. Resistance can be subdivided into three separate categories: ● Intrinsic resistance— mechanisms hard coded into all members of a bacterial species at the chromosomal level. If an organism’s antibiogram suggests susceptibility to an agent to which it should be intrinsically resistant, further work should be done to check that the identification is correct. Examples include gram-negative bacteria being resistant to glycopeptides due to the outer cell membrane, anaerobes being resistant to aminoglycosides due to lack of an uptake mechanism, and amoxicillin resistance in Klebsiella due to beta-lactamase production. ● Mutational resistance—resistance that arises randomly due to DNA replication errors in conjunction with selection pressure applied by antimicrobial agents. This is the basis of the majority of the mechanisms detailed in this chapter. ● Transferrable resistance— mutational resistance that is passed horizontally from the bacterium in which it arose to another cell, possibly of a different species entirely. This happens through either transposons (DNA that incorporates into the bacterial chromosome) or plasmids (rings of DNA that replicate independent of the main chromosome).

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Substrate Specificities and Efflux Efficiencies of RND Efflux Pumps ofAcinetobacter baumannii

Journal of Bacteriology ◽

10.1128/jb.00049-18 ◽

2018 ◽

Vol 200 (13) ◽

pp. e00049-18 ◽

Cited By ~ 17

Author(s):

Inga V. Leus ◽

Jon W. Weeks ◽

Vincent Bonifay ◽

Lauren Smith ◽

Sophie Richardson ◽

...

Keyword(s):

Antibiotic Resistance ◽

Efflux Pump ◽

Efflux Pumps ◽

Antibacterial Activities ◽

Permeability Barrier ◽

Bacterial Cells ◽

Content Type ◽

Active Efflux ◽

Rnd Efflux Pumps ◽

The Impact

ABSTRACTAntibiotic-resistantAcinetobacter baumanniicauses infections that are extremely difficult to treat. A significant role in these resistance profiles is attributed to multidrug efflux pumps, especially those belonging to the resistance-nodulation-cell division (RND) superfamily of transporters. In this study, we analyzed functions and properties of RND efflux pumps inA. baumanniiATCC 17978. This strain is susceptible to antibiotics and does not contain mutations that are commonly selected upon exposure to high concentrations of antibiotics. We constructed derivatives of ATCC 17978 lacking chromosomally encoded RND pumps and complemented these strains by the plasmid-borne genes. We analyzed the substrate selectivities and efficiencies of the individual pumps in the context of native outer membranes and their hyperporinated variants. Our results show that inactivation of AdeIJK provides the strongest potentiation of antibiotic activities, whereas inactivation of AdeFGH triggers the overexpression of AdeAB. The plasmid-borne overproduction complements the hypersusceptible phenotypes of the efflux deletion mutants to the levels of the parental ATCC 17978. Only a few antibiotics strongly benefitted from the overproduction of efflux pumps and antibacterial activities of some of those depended on the synergistic interaction with the low permeability barrier of the outer membrane. Either overproduction or inactivation of efflux pumps change dramatically the lipidome of ATCC 17978. We conclude that efflux pumps ofA. baumanniiare tightly integrated into physiology of this bacterium and that clinical levels of antibiotic resistance inA. baumanniiisolates are unlikely to be reached solely due to the overproduction of RND efflux pumps.IMPORTANCERND-type efflux pumps are important contributors in development of clinical antibiotic resistance inA. baumannii. However, their specific roles and the extent of contribution to antibiotic resistance remain unclear. We analyzed antibacterial activities of antibiotics in strains with different permeability barriers and found that the role of active efflux in antibiotic resistance ofA. baumanniiis limited to a few select antibiotics. Our results further show that the impact of efflux pump overproduction on antibiotic susceptibility is significantly lower than the previously reported for clinical isolates. Additional mechanisms of resistance, in particular those that improve the permeability barriers of bacterial cells and act synergistically with active efflux pumps are likely involved in antibiotic resistance of clinicalA. baumanniiisolates.

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Modulation of Gut Microbiota through Dietary Phytochemicals as a Novel Anti-infective Strategy

Current Drug Discovery Technologies ◽

10.2174/1570163816666191107124214 ◽

2020 ◽

Vol 17 (4) ◽

pp. 498-506 ◽

Cited By ~ 2

Author(s):

Pavan K. Mujawdiya ◽

Suman Kapur

Keyword(s):

Microbial Community ◽

Quorum Sensing ◽

Population Density ◽

Gut Microbiota ◽

Biofilm Formation ◽

Chemical Interaction ◽

Bacterial Species ◽

Critical Role ◽

Bacterial Cells ◽

Gut Microbes

: Quorum Sensing (QS) is a phenomenon in which bacterial cells communicate with each other with the help of several low molecular weight compounds. QS is largely dependent on population density, and it triggers when the concentration of quorum sensing molecules accumulate in the environment and crosses a particular threshold. Once a certain population density is achieved and the concentration of molecules crosses a threshold, the bacterial cells show a collective behavior in response to various chemical stimuli referred to as “auto-inducers”. The QS signaling is crucial for several phenotypic characteristics responsible for bacterial survival such as motility, virulence, and biofilm formation. Biofilm formation is also responsible for making bacterial cells resistant to antibiotics. : The human gut is home to trillions of bacterial cells collectively called “gut microbiota” or “gut microbes”. Gut microbes are a consortium of more than 15,000 bacterial species and play a very crucial role in several body functions such as metabolism, development and maturation of the immune system, and the synthesis of several essential vitamins. Due to its critical role in shaping human survival and its modulating impact on body metabolisms, the gut microbial community has been referred to as “the forgotten organ” by O`Hara et al. (2006) [1]. Several studies have demonstrated that chemical interaction between the members of bacterial cells in the gut is responsible for shaping the overall microbial community. : Recent advances in phytochemical research have generated a lot of interest in finding new, effective, and safer alternatives to modern chemical-based medicines. In the context of antimicrobial research various plant extracts have been identified with Quorum Sensing Inhibitory (QSI) activities among bacterial cells. This review focuses on the mechanism of quorum sensing and quorum sensing inhibitors isolated from natural sources.

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Antimicrobial Resistance among Neonates with Bacterial Sepsis and Their Clinical Outcomes in a Tertiary Hospital in Kathmandu Valley, Nepal

Tropical Medicine and Infectious Disease ◽

10.3390/tropicalmed6020056 ◽

2021 ◽

Vol 6 (2) ◽

pp. 56

Author(s):

Bijendra Raj Raghubanshi ◽

Karuna D. Sagili ◽

Wai Wai Han ◽

Henish Shakya ◽

Priyanka Shrestha ◽

...

Keyword(s):

Antibiotic Resistance ◽

Neonatal Sepsis ◽

Bacterial Culture ◽

Bacterial Species ◽

Antibiotic Sensitivity ◽

College Teaching ◽

Hospital Treatment ◽

Resistant Bacteria ◽

Coagulase Negative Staphylococcus ◽

Cross Sectional

Globally, antibiotic resistance in bacteria isolated from neonatal sepsis is increasing. In this cross-sectional study conducted at a medical college teaching hospital in Nepal, we assessed the antibiotic resistance levels in bacteria cultured from neonates with sepsis and their in-hospital treatment outcomes. We extracted data of neonates with sepsis admitted for in-patient care from June 2018 to December 2019 by reviewing hospital records of the neonatal intensive care unit and microbiology department. A total of 308 neonates with sepsis were admitted of which, blood bacterial culture antibiotic sensitivity reports were available for 298 neonates. Twenty neonates (7%) had bacteriologic culture-confirmed neonatal sepsis. The most common bacterial species isolated were Staphylococcus aureus (8), followed by coagulase-negative Staphylococcus (5). Most of these bacteria were resistant to at least one first-line antibiotic used to manage neonatal sepsis. Overall, there were 7 (2%) deaths among the 308 neonates (none of them from the bacterial culture-positive group), and 53 (17%) neonates had left the hospital against medical advice (LAMA). Improving hospital procedures to isolate bacteria in neonates with sepsis, undertaking measures to prevent the spread of antibiotic-resistant bacteria, and addressing LAMA’s reasons are urgently needed.

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Precise regulation of the relative rates of surface area and volume synthesis in bacterial cells growing in dynamic environments

Nature Communications ◽

10.1038/s41467-021-22092-5 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Handuo Shi ◽

Yan Hu ◽

Pascal D. Odermatt ◽

Carlos G. Gonzalez ◽

Lichao Zhang ◽

...

Keyword(s):

Growth Rate ◽

Time Delay ◽

Surface Area ◽

Environmental Changes ◽

Volume Ratio ◽

Dynamic Environments ◽

Bacterial Cells ◽

Bacterial Growth Rate ◽

State Size ◽

Insight Into

AbstractThe steady-state size of bacterial cells correlates with nutrient-determined growth rate. Here, we explore how rod-shaped bacterial cells regulate their morphology during rapid environmental changes. We quantify cellular dimensions throughout passage cycles of stationary-phase cells diluted into fresh medium and grown back to saturation. We find that cells exhibit characteristic dynamics in surface area to volume ratio (SA/V), which are conserved across genetic and chemical perturbations as well as across species and growth temperatures. A mathematical model with a single fitting parameter (the time delay between surface and volume synthesis) is quantitatively consistent with our SA/V experimental observations. The model supports that this time delay is due to differential expression of volume and surface-related genes, and that the first division after dilution occurs at a tightly controlled SA/V. Our minimal model thus provides insight into the connections between bacterial growth rate and cell shape in dynamic environments.

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