scholarly journals Interventions on Metabolism: Making Antibiotic-Susceptible Bacteria

mBio ◽  
2017 ◽  
Vol 8 (6) ◽  
Author(s):  
Fernando Baquero ◽  
José-Luis Martínez

ABSTRACT Antibiotics act on bacterial metabolism, and antibiotic resistance involves changes in this metabolism. Interventions on metabolism with drugs might therefore modify drug susceptibility and drug resistance. In their recent article, Martin Vestergaard et al. (mBio 8:e01114-17, 2017, https://doi.org/10.1128/mBio.01114-17 !) illustrate the possibility of converting intrinsically resistant bacteria into susceptible ones. They reported that inhibition of a central metabolic enzyme, ATP synthase, allows otherwise ineffective polymyxin antibiotics to act on Staphylococcus aureus. The study of the intrinsic resistome of bacterial pathogens has shown that several metabolic genes, including multigene transcriptional regulators, contribute to antibiotic resistance. In some cases, these genes only marginally increase antibiotic resistance, but reduced levels of susceptibility might be critical in the evolution or resistance under low antibiotic concentrations or in the clinical response of highly resistant bacteria. Drug interventions on bacterial metabolism might constitute a critical adjuvant therapy in combination with antibiotics to ensure susceptibility of pathogens with intrinsic or acquired antimicrobial resistance.

mSystems ◽  
2020 ◽  
Vol 5 (3) ◽  
Author(s):  
Teresa Gil-Gil ◽  
Fernando Corona ◽  
José Luis Martínez ◽  
Alejandra Bernardini

ABSTRACT Fosfomycin is a bactericidal antibiotic, analogous to phosphoenolpyruvate, that exerts its activity by inhibiting the activity of MurA. This enzyme catalyzes the first step of peptidoglycan biosynthesis, the transfer of enolpyruvate from phosphoenolpyruvate to uridine-diphosphate-N-acetylglucosamine. Fosfomycin is increasingly being used, mainly for treating infections caused by Gram-negative multidrug-resistant bacteria. The mechanisms of mutational resistance to fosfomycin in Stenotrophomonas maltophilia, an opportunistic pathogen characterized by its low susceptibility to commonly used antibiotics, were studied in the current work. None of the mechanisms reported so far for other organisms, which include the production of fosfomycin-inactivating enzymes, target modification, induction of an alternative peptidoglycan biosynthesis pathway, and the impaired entry of the antibiotic, are involved in the acquisition of such resistance by this bacterial species. Instead, the unique cause of resistance in the mutants studied is the mutational inactivation of different enzymes belonging to the Embden-Meyerhof-Parnas central metabolism pathway. The amount of intracellular fosfomycin accumulation did not change in any of these mutants, showing that neither inactivation nor transport of the antibiotic is involved. Transcriptomic analysis also showed that the mutants did not present changes in the expression level of putative alternative peptidoglycan biosynthesis pathway genes or any related enzyme. Finally, the mutants did not present an increased phosphoenolpyruvate concentration that might compete with fosfomycin for its binding to MurA. On the basis of these results, we describe a completely novel mechanism of antibiotic resistance based on mutations of genes encoding metabolic enzymes. IMPORTANCE Antibiotic resistance has been largely considered a specific bacterial response to an antibiotic challenge. Indeed, its study has been mainly concentrated on mechanisms that affect the antibiotics (mutations in transporters, efflux pumps, and antibiotic-modifying enzymes, or their regulators) or their targets (i.e., target mutations, protection, or bypass). Usually, antibiotic resistance-associated metabolic changes were considered a consequence (fitness costs) and not a cause of antibiotic resistance. Herein, we show that alterations in the central carbon bacterial metabolism can also be the cause of antibiotic resistance. In the study presented here, Stenotrophomonas maltophilia acquires fosfomycin resistance through the inactivation of glycolytic enzymes belonging to the Embden-Meyerhof-Parnas pathway. Besides resistance to fosfomycin, this inactivation also impairs the bacterial gluconeogenic pathway. Together with previous work showing that antibiotic resistance can be under metabolic control, our results provide evidence that antibiotic resistance is intertwined with the bacterial metabolism.


2020 ◽  
Vol 10 (01) ◽  
pp. 106-113
Author(s):  
Hussain A. Hamza ◽  
Nasreen R. Jber

Methicillin-resistant Staphylococcus aureus (MRSA) is a S. aureus that resistant to β-lactam antibiotics (e.g., Cefoxitin and Oxacillin). MRSA has a tremendous capacity to develop resistance to other classes of antibiotics and forming a real threat to patients. The process of exploring a new tactic of non-antibiotic treatments has become an urgent need. A bacteriophage is one of the possible treatments that strongly suggested. Bacteriophages are viruses that infect bacteria as a natural host with a bactericidal capability against multidrug-resistant bacteria that do not respond to conventional antibiotics. The current study investigates the lytic efficacy of phage-cocktail in vitro, specifically against S. aureus isolated from skin infections and find out the possible association of phage-antibiotic resistance. A total of 43 isolates of Methicillin-resistant staphylococcus aureus were isolated from skin infections. The isolates are distributed as (10 isolates of burn, 4 isolates of diabetic foot ulcer, 7 isolates of surgical wounds, 3 isolates of pressure ulcer, and 19 of skin and soft tissue infection). The isolates exhibited variant antibiotic susceptibility against 12 antibiotics (Cefoxitin FOX, Vancomycin VAN, Oxacillin OX, Rifampin RA, Chloramphenicol C, Nitrofurantoin F, Clindamycin DA, Azithromycin AZM, Amikacin AK, Trimethoprim-sulfamethoxazole SXT, Ciprofloxacin CIP, and Gentamicin CN). A bacteriophage cocktail was isolated using a phage-enrichment technique, high titer phage lysate (5*109 pfu/ml) was obtained and investigated against 43 MRSA isolates. The phage-cocktail showed high specificity to S. aureus but variable susceptibility to 43 MRSA isolates. It was observed that there was no association (p greater than 0.05) between phage and antibiotic resistance of (FOX, OX, VAN, RA, C, F, and DA) where the significant association was observed (p less than 0.05) with (AZM, AK, SXT, CIP, and CN). Significantly, the more antibiotic-resistant isolates exhibited more sensitivity to phage-cocktail, which represents a promising alternative to antibiotics that do not affect with increasing antibiotic resistance.


2019 ◽  
Vol 6 (2) ◽  
pp. 727
Author(s):  
Senthil Kumar K. ◽  
Ajith Brabhu Kumar C.

Background: Methicillin resistant Staphylococcus aureus (MRSA) is endemic in India and is a dangerous pathogen for hospital acquired infections. Analysing antibiotic susceptibility pattern of Staphylococcus helps us to overcome the therapeutic difficulties created by the rising anti-microbial resistant bacteria and guide us in choosing appropriate antibiotics. Hence, this study was conducted.Methods: Children with confirmed S. aureus infection between the age group of 0-12 years were classified into MSSA and MRSA subgroups. Isolates were identified as S. aureus using standard microbiological methodologies at diagnostic bacteriology laboratory, in the Microbiology department. Basic demographic variables and antibiotic resistance patterns were compared between MRSA and MSSA subgroups.Results: Majority of S. aureus were isolated from pus followed by blood culture. Prevalence of community acquired MRSA in present study (80%, with 95% CI from 68.56% to 91.44%) was significantly higher when compared to another studies (p value=0.004). Resistance to gentamicin and ciprofloxacin among the MRSA isolates was more than that in methicillin sensitive S. aureus (MSSA) (P<0.001).Conclusions: It is prudent to include MRSA coverage in empirical antibiotic regimens in settings where a significant proportion of patients hospitalized for S. aureus infection have MRSA.


2020 ◽  
Vol 7 (11) ◽  
pp. 5085-5094
Author(s):  
Mahamat Ali Hassan ◽  
Cheikna ZONGO ◽  
Ali Haroun Hissein ◽  
Yeri Esther HIEN ◽  
Denis Erbi ◽  
...  

Surgical Site Infections (SSI) are caused in most cases by the resistant or multi-resistant bacteria. Gravities go from a simple superficial cutaneous infection to the potentially deadly infections as the stern septicemia. The objective of this survey is to study the antibiorésistance of germs implied in infections of the operative site to the General Hospital of National Reference (HGRN) of Ndjamena to Chad . The survey had taken place of July to November 2018. A total of 51 cases of infections of the Surgical Sites has been recorded then appropriated and sowed on the Chapman, Mac Conkey, gélose to the Cétrimide, Sabouraud and chocolate gelose in view of an isolation of germs implied. The classic gallery, the API20ES gallery permitted the identification of the different stumps. The classic antibiogramm on a middle gelose of Muller Hinton permitted the survey of the antibiorésistance.  The Vitek2 permitted the confirmation of identification, the survey of the antibiorésistance and the detection of stumps of betalactamases enterobacteries producers. The implied germs were: E. coli (29,4%), follow-up of Klebsiella spp (22,5%), Staphylococcus aureus (16,6%), Pseudomonas aeroginosa (11,7%), Proteus mirabilis (8,8%), Enterobacter cloacae (5,8%), Serratia odorifera, Shigella sonnei, Corynebacterium spp (0,98%) each, Candida albicans (1,9%). The identified germs multiresistantes were E. coli, Klebsiella spp, Enterobacter cloacae, Serratia odorifera and Shigella spp. A level of resistance (4%) to the imipenème at entérobactérieses has been recorded. One also notes a resistant of stumps of Staphylococcus aureus 100% to the penicillin and the oxacilline, as well as a resistance to the vancomycine (3%).   The identification of stumps isolated showed that the stump E. coli (29,4%) is the germ the more implied. Also, the survey of the antibiorésistance permitted to note a strong resistance of bacteria isolated opposite the tested antibiotics.    Surgical site infections (SSI) are caused in most cases by resistant or multi-resistant bacteria. Gravities range from simple superficial skin infections to potentially fatal infections such as severe sepsis. The objective of this study is to study the antibiotic resistance of germs involved in surgical site infections at the Hôpital Général de Référence Nationale (HGRN) in Ndjamena, Chad.   The study took place from July to November 2018. A total of 51 surgical site infections were recorded, then sampled and inoculated on Chapman, Mac Conkey, Cetrimid agar, Sabouraud and chocolate agar media to isolate the germs involved. The classical gallery, the API20E gallery allowed the identification of the different strains. The classical antibiogram on a Muller Hinton agar medium allowed the study of antibiotic resistance.   Vitek2 enabled confirmation of the identification, study of antibiotic resistance and detection of strains of enterobacteria producing beta-lactamases. The frequency of surgical site infections obtained was 33.6% (51/152). The germs involved were: E. coli (29.4%), followed by Klebsiella spp (22.5%), Staphylococcus aureus (16.6%), Pseudomonas aeroginosa (11.7%), Proteus mirabilis (8.8%), Enterobacter cloacae (5.8%), Serratia odorifera, Shigella sonnei, Corynebacterium spp (0.98%) each, Candida albicans (1.9%). The multi-resistant germs identified were: E. coli, Klebsiella spp, Enterobacter cloacae, Serratia odorifera and Shigella spp. A level of resistance (4%) to imipenem in Enterobacteriaceae was recorded. Resistance of Staphylococcus aureus strains to penicillin and oxacillin (100%) and resistance to vancomycin (3%) were also noted The identification of the strains isolated showed that the E. coli strain (29.4%) is the most involved germ. Also, the study of antibiotic resistance showed that the bacteria isolated were highly resistant to the antibiotics tested.


Author(s):  
Ezekiel Kofi Vicar ◽  
Patrick K. Feglo ◽  
Samuel E. K. Acquah ◽  
Walana Williams ◽  
Courage K. S. Saba ◽  
...  

The presence of antimicrobial resistant foodborne bacteria is a major food safety challenge for food that is consumed raw. Abuse and overuse of antibiotics in the agriculture sector has been identified as a contributory factor to the rising threat of antibiotic resistance. In many developing countries where milk is marketed and consumed raw through informal channels, the occurrence of bacterial contamination is high and poses a major public health risk. This situation is exacerbated when caused by antimicrobial resistant bacteria. Hence this study was conducted to determine the antimicrobial resistant pattern of bacteria in raw cow milk and milk products retailed in the Northern Region of Ghana. Antibiotic resistance profiles were established for 150 bacteria isolates (Escherichia coli, E. coli O157:H7, Klebsiella pneumonia, Staphylococcus aureus, Pseudomonas aeruginosa, Salmonella spp. Shigella spp. and Proteus spp.) obtained from the culture of raw milk (n=210) and milk products (n=60) retailed within the Northern region of Ghana. Susceptibility to nine antimicrobials commonly used in veterinary and human medical practice was performed on all the isolates using the agar disc diffusion method according to Clinical and Laboratory Standards Institute guidelines. Isolates showed highest resistance to Nalidixic acid followed by Chloramphenicol, Gentamicin, Trimethoprim-sulfamethoxazole and Ceftriaxone but were most susceptible to Ciprofloxacin and Ampicillin. About 25 – 47.6 % of Staphylococcus aureus showed resistance to Cefoxitin. Milk and milk products sold in the northern region of Ghana are contaminated with bacterial pathogens with high levels of antimicrobial resistance. A one health approach is required to curtail the threat of antibacterial resistant bacteria in the food chain.


2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Oloufemi Daniel Ichola ◽  
Victorien Tamegnon Dougnon ◽  
Charles Hornel Koudokpon ◽  
Alidehou Jerrold Agbankpe ◽  
Esther Deguenon ◽  
...  

The study aims to document the level of contamination of the aquatic ecosystem of the Cotonou-Lake Nokoué canal hydrographic complex by multidrug-resistant bacteria and their resistance genes. For this purpose, water samples were taken from several points of the complex and from the sediments at the depth of the lake. Samples of several species of freshly caught fish products from the lake were also collected. Bacteriological analyses were carried out according to the AFNOR standard (NF U: 47–100). The identification of the different bacterial species isolated was then carried out using the API 20E gallery and specific biochemical tests. The antibiogram of the strains was performed according to the recommendations of the EUCAST. Molecular characterization of the identified strains was carried out by searching for resistance and virulence genes. The results obtained revealed the presence of several bacterial species in water samples and in sediment and intestine samples of fishery products with a predominance of Gram-negative bacilli. The resistance profile of Gram-negative bacilli showed a total resistance to metronidazole (100%). 23% of the strains were also resistant to ciprofloxacin, 41% to amoxicillin, and 60% to aztreonam. Of the Gram-positive cocci identified, 66% was resistant to vancomycin, 7.5% to ciprofloxacin, 71% to erythromycin, and 22% to tetracycline. Regarding the genes sought, blaTEM (46%), blaSHV (24%), and blaCTX-M-15 (31%) were present in the genome of Gram-negative bacilli as resistance genes and fimH (41%) as virulence gene. As for Gram-positive cocci, the van B gene was completely absent. The van A was present at 6.25% in Staphylococcus aureus and mecA at 21.88 and 33.33%, respectively, in Staphylococcus aureus and coagulase-negative staphylococci strains. The high resistance of isolated bacterial strains is a matter of concern and calls for a rational use of antibiotics in order to avoid the transmission of antibiotic resistance from the environment to humans.


Polymers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 2127
Author(s):  
Jael Fernandez ◽  
Ángela Martin-Serrano ◽  
Natalia Gómez-Casanova ◽  
Annarita Falanga ◽  
Stefania Galdiero ◽  
...  

Antibiotic resistance and biofilm-related infections, persistent in conventional antimicrobial treatment, are continuously increasing and represent a major health problem worldwide. Therefore, the development of new effective treatments to prevent and treat biofilm-related infections represents a crucial challenge. Unfortunately, the extensive use of antibiotics has led to an increase of resistant bacteria with the subsequent loss of effectivity of commercial antibiotics, mainly due to antibiotic resistance and the ability of some bacteria to form microbial communities in biotic or abiotic surfaces (biofilms). In some cases, these biofilms are resistant to high concentrations of antibiotics that lead to treatment failure and recurrence of the associated infections. In the fight against microbial resistance, the combination of traditional antibiotics with new compounds (combination therapy) is an alternative that is becoming more extensive in the medical field. In this work, we studied the cooperative effects between levofloxacin, an approved antibiotic, and peptides or cationic dendritic molecules, compounds that are emerging as a feasible solution to overcome the problem of microbial resistance caused by pathogenic biofilms. We studied a new therapeutic approach that involves the use of levofloxacin in combination with a cationic carbosilane dendron, called MalG2(SNHMe2Cl)4, or a synthetic cell-penetrating peptide, called gH625, conjugated to the aforementioned dendron. To carry out the study, we used two combinations (1) levofloxacin/dendron and (2) levofloxacin/dendron-peptide nanoconjugate. The results showed the synergistic effect of the combination therapy to treat Staphylococcus aureus biofilms. In addition, we generated a fluorescein labeled peptide that allowed us to observe the conjugate (dendron-peptide) localization throughout the bacterial biofilm by confocal laser scanning microscopy.


Antibiotics ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 682
Author(s):  
Hun-Suk Song ◽  
Tae-Rim Choi ◽  
Shashi Kant Bhatia ◽  
Sun Mi Lee ◽  
Sol Lee Park ◽  
...  

The overuse of antibiotics has led to the emergence of multidrug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA). MRSA is difficult to kill with a single antibiotic because it has evolved to be resistant to various antibiotics by increasing the PBP2a (mecA) expression level, building up biofilm, introducing SCCmec for multidrug resistance, and changing its membrane properties. Therefore, to overcome antibiotic resistance and decrease possible genetic mutations that can lead to the acquisition of higher antibiotic resistance, drug combination therapy was applied based on previous results indicating that MRSA shows increased susceptibility to free fatty acids and surfactants. The optimal ratio of three components and the synergistic effects of possible combinations were investigated. The combinations were directly applied to clinically isolated strains, and the combination containing 15 μg/mL of oxacillin was able to control SCCmec type III and IV isolates having an oxacillin minimum inhibitory concentration (MIC) up to 1024 μg/mL; moreover, the combination with a slightly increased oxacillin concentration was able to kill SCCmec type II. Phospholipid analysis revealed that clinical strains with higher resistance contained a high portion of 12-methyltetradecanoic acid (anteiso-C15:0) and 14-methylhexadecanoic acid (anteiso-C17:0), although individual strains showed different patterns. In summary, we showed that combinatorial therapy with a low concentration of oxacillin controlled different laboratory and highly diversified clinical MRSA strains.


2019 ◽  
Author(s):  
Teresa Gil-Gil ◽  
Fernando Corona ◽  
José Luis Martínez ◽  
Alejandra Bernardini

AbstractFosfomycin is a bactericidal antibiotic, analogous to phosphoenolpyruvate (PEP) that exerts its activity by inhibiting the activity of MurA. This enzyme catalyzes the first step of peptidoglycan biosynthesis, the transfer of enolpyruvate from PEP to uridine-diphosphate-N-acetylglucosamine. Fosfomycin is increasingly used in the last years, mainly for treating infections caused by Gram-negative multidrug resistant bacteria as Stenotrophomonas maltophilia, an opportunistic pathogen characterized by its low susceptibility to antibiotics of common use. The mechanisms of mutational resistance to fosfomycin in S. maltophilia were studied in the current work. None of the mechanisms so far described for other organisms, which include the production of fosfomycin inactivating enzymes, target modification, induction of alternative peptidoglycan biosynthesis pathway and the impaired entrance of the antibiotic, are involved in the acquisition of such resistance by this bacterial species. Rather the unique cause of resistance in the studied mutants is the mutational inactivation of different enzymes belonging to the Embden-Meyerhof-Parnas central metabolism pathway. The amount of intracellular fosfomycin accumulation did not change in any of these mutants showing that neither the inactivation nor the transport of the antibiotic were involved. Transcriptomic analysis also showed that the mutants did not present changes in the expression level of putative alternative peptidoglycan biosynthesis pathway genes neither any related enzyme. Finally, the mutants did not present an increased PEP concentration that might compete with fosfomycin for its binding to MurA. Based on these results, we describe a completely novel mechanism of antibiotic resistance based on the remodeling of S. maltophilia metabolism.SignificanceAntibiotic resistance (AR) has been largely considered as a specific bacterial response to an antibiotic challenge. Indeed, its study has been mainly concentrated in mechanisms that affect the antibiotics (mutations in transporters, the activity of efflux pumps and antibiotic modifying enzymes) or their targets (i.e.: target mutations, protection or bypass). Usually, AR-associated metabolic changes were considered to be a consequence (fitness costs) and not a cause of AR. Herein, we show that strong alterations in the bacterial metabolism can also be the cause of AR. In the study here presented, Stenotrophomonas maltophilia acquires fosfomycin resistance through the inactivation of glycolytic enzymes belonging to the Embden-Meyerhof-Parnas. Besides resistance to fosfomycin, this inactivation also impairs the bacterial gluconeogenic pathway. Together with previous work showing that AR can be under metabolic control, our results provide evidence that AR is intertwined with the bacterial metabolism.


2020 ◽  
Vol 7 (4) ◽  
pp. 104-108
Author(s):  
Bahram Askarpour ◽  
Alireza Sedaghat ◽  
Nazanin Hazrati ◽  
Ali Ahmadabadi ◽  
Masoud Youssefi ◽  
...  

Background: Burn remains a globally significant life-threatening problem, especially in developing countries, and infection is considered as a major complication among burn patients. The rate of antibiotic-resistant bacteria isolated from burn patients has demonstrated a significant increase. In this regard, this study aimed to determine the antibiotic resistance pattern in Staphylococcus aureus isolated from patients’ burn wound infections. Methods: All available wound cultures of burn patients admitted to the burn unit of Emam-Reza hospital/ Mashhad, northeast Iran from March 2012 to March 2017 were included in this retrospective study. Then, the resistance of isolated S. aureus strains against 25 different antibiotic disks was studied based on the aim of the study. Results: Overall, 1973 patients were admitted, out of whom 4758 swab samples were taken from them. Out of 3188 micro-organisms isolated from burn wound cultures, 185 (5.8%) cases were S. aureus. Based on the results, the highest susceptibility rates were related to vancomycin (98.8%), cefazolin (72%), ciprofloxacin (75%), and gentamicin (74.6%). Conclusions: In general, vancomycin, cefazolin, and ciprofloxacin appeared to be the most effective agents among all tested antibiotics for S. aureus. The extensive use of antibiotics in treating infections has resulted in the emergence of resistant strains. Routine microbiological surveillance and careful in vitro testing before antibiotic use may help in the prevention of the ever-increasing antibiotic-resistant pathogens in burn infections.


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