Mechanisms of antibiotic resistance in Gram-positive bacteria

The increase in antibiotic resistance among Gram-positive bacteria underscores the urgent need to develop new antibiotics. New antibiotics should target actively growing susceptible bacteria that are resistant to clinically accepted antibiotics including bacteria that are not growing or are protected in a biofilm environment. In this paper, we compare the in vitro activities of two new semisynthetic glycopeptide antibiotics, MA79 and ERJ390, with two clinically used glycopeptide antibiotics—vancomycin and teicoplanin. The new antibiotics effectively killed not only exponentially growing cells of Staphylococcus aureus, but also cells in the stationary growth phase and biofilm.

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Medicinal Chemistry Updates on Bacterial Efflux Pump Modulators

Current Medicinal Chemistry ◽

10.2174/0929867325666180209142612 ◽

2019 ◽

Vol 25 (42) ◽

pp. 6030-6069 ◽

Cited By ~ 7

Author(s):

Fernando Durães ◽

Madalena Pinto ◽

Emília Sousa

Keyword(s):

Energy Source ◽

Antibiotic Resistance ◽

Efflux Pump ◽

Efflux Pumps ◽

The Other ◽

Drug Uptake ◽

Health Issues ◽

Gram Positive ◽

Gram Positive Bacteria ◽

Efflux Pump Inhibitors

Antibiotic resistance is one of the most pressing health issues of our days. It can arise due to a multiplicity of factors, such as target modification, decrease in the drug uptake, changes in the metabolic pathways and activation of efflux pumps. The overexpression of efflux pumps is responsible for the extrusion of drugs, making antibiotic therapy fail, as the quantity of intracellular antibiotic is not enough to provide the desired therapeutic effect. Efflux pumps can be included in five families according to their composition, nature of substrates, energy source, and number of transmembrane spanning regions. The ABC superfamily is mainly found in Gram-positive bacteria, use ATP as an energy source, and only a limited number of ABC pumps confer multidrug resistance (MDR). On the other hand, the MFS family, most present in Gram-positive bacteria, and the RND family, characteristic of Gram-negative bacteria, are most associated with antibiotic resistance. A wide variety of inhibitors have been disclosed for both families, from either natural or synthetic sources, or even drugs that are currently in therapy for other diseases. The other two families are the SMR, which are the smallest drug efflux proteins known, and the MATE family, whose pumps can also resort to the sodium gradient as an energy source. In this review, it is intended to present a comprehensive review of the classes of efflux pump inhibitors from the various sources, highlighting their structure-activity relationships, which can be useful for medicinal chemists in the pursuit of novel efflux pump inhibitors.

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Structural basis of resistance to lincosamide, streptogramin A, and pleuromutilin antibiotics by ABCF ATPases in Gram-positive pathogens

10.1101/2020.11.24.396648 ◽

2020 ◽

Author(s):

Caillan Crowe-McAuliffe ◽

Victoriia Murina ◽

Kathryn Jane Turnbull ◽

Marje Kasari ◽

Merianne Mohamad ◽

...

Keyword(s):

Antibiotic Resistance ◽

Ribosomal Subunit ◽

Structural Basis ◽

Comparative Approach ◽

Host Organism ◽

Large Ribosomal Subunit ◽

Gram Positive ◽

Present Evidence ◽

Gram Positive Bacteria ◽

Peptidyltransferase Center

AbstractTarget protection proteins bind to antibiotic targets and confer resistance to the host organism. One class of such proteins, termed antibiotic resistance (ARE) ATP binding cassette (ABC) proteins of the F-subtype (ARE ABCFs), are widely distributed throughout Gram-positive bacteria and bind the ribosome to alleviate translational inhibition by antibiotics that target the large ribosomal subunit. Using single-particle cryo-EM, we have solved the structure of ARE ABCF–ribosome complexes from three Gram-positive pathogens: Enterococcus faecalis LsaA, Staphylococcus haemolyticus VgaALC and Listeria monocytogenes VgaL. Supported by extensive mutagenesis analysis, these structures enable a comparative approach to understanding how these proteins mediate antibiotic resistance on the ribosome. We present evidence of mechanistically diverse allosteric relays converging on a few peptidyltransferase center (PTC) nucleotides, and propose a general model of antibiotic resistance mediated by these ARE ABCFs.

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Pattern of antibiotic resistance of various strains of bacteria causing acute tonsillitis

International Journal of Otorhinolaryngology and Head and Neck Surgery ◽

10.18203/issn.2454-5929.ijohns20212122 ◽

2021 ◽

Vol 7 (6) ◽

pp. 994

Author(s):

N. Jyothsna ◽

A. Ramya ◽

K. Abhilash ◽

Bathsa Liza Johnson

Keyword(s):

Antibiotic Resistance ◽

Bacterial Growth ◽

Bacterial Strain ◽

Gram Negative Bacteria ◽

Gram Positive ◽

Acute Tonsillitis ◽

Gram Negative ◽

Gram Positive Bacteria ◽

Antibiotic Drugs ◽

Significant Difference

Background: Our study was done to determine the pattern of antibiotic resistance of various strains of bacteria causing acute tonsillitis.Methods: the study was a randomized cross sectional study. Patients matching the inclusion criteria were included. Duration of study was 6 months.Results: Out of 120 cases, 46 cases showed no bacterial growth (NBG) and 74 cases showed bacterial growth. 42 cases were gram-negative bacterial strain and 32 cases were positive bacterial strain out of 72 bacterial grown cases. A list of 25 antibiotic drugs in gram-negative and 31 drugs in gram-positive strain, their sensitivity and resistance were taken and noted. Among gram-negative bacteria imipenem (71.4%) showed highest sensitivity. Highest antibiotic resistance was seen in ampicillin (85.71%). Least sensitivity is observed in clindamycin, amoxicillin+clavulanic acid with 2.38%. Among gram-positive bacteria, highest sensitivity was noted in cefotaxime (75%). Highest antibiotic resistance was seen in cotrimoxazole (46.8%). Least sensitivity is observed in netilmicin, sulbactam with 3.12%.Conclusions: The number of drugs resistant to the gram-positive bacteria are lesser than number of drugs sensitive, which showed significant difference (p<0.05). Significant difference of antibiotic drugs was not found in gram-negative bacteria. Our study findings helped in appropriate and guarded use of the antibiotic drugs in acute tonsillitis, minimizing the exposure of individuals to antibiotic resistance by choosing an appropriate sensitive drug, therefore improving the quality of therapy.

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A Conserved Class II Type Thioester Domain-Containing Adhesin Is Required for Efficient Conjugation in Bacillus subtilis

mBio ◽

10.1128/mbio.00104-21 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

César Gago-Córdoba ◽

Jorge Val-Calvo ◽

David Abia ◽

Alberto Díaz-Talavera ◽

Andrés Miguel-Arribas ◽

...

Keyword(s):

Antibiotic Resistance ◽

Bacillus Subtilis ◽

Recipient Cell ◽

Class Ii ◽

Pair Formation ◽

Conjugative Plasmid ◽

Mating Pair ◽

Gram Positive ◽

Content Type ◽

Gram Positive Bacteria

ABSTRACT Conjugation, the process by which a DNA element is transferred from a donor to a recipient cell, is the main horizontal gene transfer route responsible for the spread of antibiotic resistance and virulence genes. Contact between a donor and a recipient cell is a prerequisite for conjugation, because conjugative DNA is transferred into the recipient via a channel connecting the two cells. Conjugative elements encode proteins dedicated to facilitating the recognition and attachment to recipient cells, also known as mating pair formation. A subgroup of the conjugative elements is able to mediate efficient conjugation during planktonic growth, and mechanisms facilitating mating pair formation will be particularly important in these cases. Conjugative elements of Gram-negative bacteria encode conjugative pili, also known as sex pili, some of which are retractile. Far less is known about mechanisms that promote mating pair formation in Gram-positive bacteria. The conjugative plasmid pLS20 of the Gram-positive bacterium Bacillus subtilis allows efficient conjugation in liquid medium. Here, we report the identification of an adhesin gene in the pLS20 conjugation operon. The N-terminal region of the adhesin contains a class II type thioester domain (TED) that is essential for efficient conjugation, particularly in liquid medium. We show that TED-containing adhesins are widely conserved in Gram-positive bacteria, including pathogens where they often play crucial roles in pathogenesis. Our study is the first to demonstrate the involvement of a class II type TED-containing adhesin in conjugation. IMPORTANCE Bacterial resistance to antibiotics has become a serious health care problem. The spread of antibiotic resistance genes between bacteria of the same or different species is often mediated by a process named conjugation, where a donor cell transfers DNA to a recipient cell through a connecting channel. The first step in conjugation is recognition and attachment of the donor to a recipient cell. Little is known about this first step, particularly in Gram-positive bacteria. Here, we show that the conjugative plasmid pLS20 of Bacillus subtilis encodes an adhesin protein that is essential for effective conjugation. This adhesin protein has a structural organization similar to adhesins produced by other Gram-positive bacteria, including major pathogens, where the adhesins serve in attachment to host tissues during colonization and infection. Our findings may thus also open novel avenues to design drugs that inhibit the spread of antibiotic resistance by blocking the first recipient-attachment step in conjugation.

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Anti-staphylococcal activity and mode of action of thioridazine photoproducts

Scientific Reports ◽

10.1038/s41598-020-74752-z ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Tatiana Tozar ◽

Sofia Santos Costa ◽

Ana-Maria Udrea ◽

Viorel Nastasa ◽

Isabel Couto ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Antibiotic Resistance ◽

Molecular Docking ◽

Infectious Diseases ◽

Molecular Mechanisms ◽

Dynamic Surface Tension ◽

Docking Studies ◽

Gram Positive ◽

Dynamic Surface ◽

Gram Positive Bacteria

Abstract Antibiotic resistance became an increasing risk for population health threatening our ability to fight infectious diseases. The objective of this study was to evaluate the activity of laser irradiated thioridazine (TZ) against clinically-relevant bacteria in view to fight antibiotic resistance. TZ in ultrapure water solutions was irradiated (1–240 min) with 266 nm pulsed laser radiation. Irradiated solutions were characterized by UV–Vis and FTIR absorption spectroscopy, thin layer chromatography, laser-induced fluorescence, and dynamic surface tension measurements. Molecular docking studies were made to evaluate the molecular mechanisms of photoproducts action against Staphylococcus aureus and MRSA. More general, solutions were evaluated for their antimicrobial and efflux inhibitory activity against a panel of bacteria of clinical relevance. We observed an enhanced antimicrobial activity of TZ photoproducts against Gram-positive bacteria. This was higher than ciprofloxacin effects for methicillin- and ciprofloxacin-resistant Staphylococcus aureus. Molecular docking showed the Penicillin-binding proteins PBP3 and PBP2a inhibition by sulforidazine as a possible mechanism of action against Staphylococcus aureus and MRSA strains, respectively. Irradiated TZ reveals possible advantages in the treatment of infectious diseases produced by antibiotic-resistant Gram-positive bacteria. TZ repurposing and its photoproducts, obtained by laser irradiation, show accelerated and low-costs of development if compared to chemical synthesis.

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