Novel Antibacterial Targets in Protein Biogenesis Pathways

Potteth, Upasana S.; Upadhyay, Tulsi; Saini, Snehlata; Saraogi, Ishu

doi:10.1002/cbic.202100459

Cited by 5 publications

(4 citation statements)

References 235 publications

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“…Infectious diseases rank as the second leading cause of global mortality, with particular concern arising from panresistant strains of Gram-negative bacteria [4]. Target-based antibiotic development has not yielded significant breakthroughs, necessitating a greater emphasis on target-based antibiotic research [5].…”

Section: Introductionmentioning

confidence: 99%

In Vitro Microevolution and Co-Selection Assessment of Florfenicol Impact on Escherichia coli Resistance Development

Kerek,

Török,

Laczkó

et al. 2023

Antibiotics

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The issue of antimicrobial resistance is becoming an increasingly serious challenge in both human and veterinary medicine. Prudent antimicrobial use in veterinary medicine is warranted and supported by international guidelines, with the Antimicrobial Advice Ad Hoc Expert Group (AMEG) placing particular emphasis on the critically important group B antimicrobials. These antimicrobials are commonly employed, especially in the poultry and swine industry. The impact of florfenicol, a veterinary antibiotic, was studied on the resistance development of Escherichia coli. The aim of the study was to investigate the effect of the use of florfenicol on the development of phenotypic and genomic resistances, not only to the drug itself but also to other drugs. The minimum inhibitory concentrations (MICs) of the antibiotics were investigated at 1×, 10×, 100× and 1000× concentrations using the adapted Microbial Evolution and Growth Arena (MEGA-plate) method. The results demonstrate that florfenicol can select for resistance to fluoroquinolone antibiotics (167× MIC value increase) and cephalosporins (67× MIC value increase). A total of 44 antimicrobial resistance genes were identified, the majority of which were consistent across the samples. Chromosomal point mutations, including alterations in resistance-associated and regulatory genes (acrB, acrR, emrR and robA), are thought to trigger multiple drug efflux pump activations, leading to phenotypically increased resistance. The study underscores the impact of florfenicol and its role in the development of antimicrobial resistance, particularly concerning fluoroquinolone antibiotics and cephalosporins. This study is the first to report florfenicol’s dose-dependent enhancement of other antibiotics’ MICs, linked to mutations in SOS-box genes (mdtABC-tolC, emrAB-tolC and acrAB-tolC) and increased multidrug efflux pump genes. Mutations in the regulatory genes acrR, emrR and rpbA support the possibility of increased gene expression. The results are crucial for understanding antimicrobial resistance and its development, highlighting the promising potential of in vitro evolutionary and coselection studies for future research.

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Section: Introductionmentioning

confidence: 99%

In Vitro Microevolution and Co-Selection Assessment of Florfenicol Impact on Escherichia coli Resistance Development

Kerek,

Török,

Laczkó

et al. 2023

Antibiotics

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“…Currently used antibiotics act on one of the pathways necessary for the survival of bacterial cells, including cell wall synthesis and the biosynthesis of nucleic acids or proteins. Due to the rapidly developing antibiotic resistance (e.g., production of enzymes inactivating antibiotics, modifications in the targeted pathways), it is important to select new biochemical and therapeutic targets for antibacterial drugs [5,20]. An interesting approach is to block the biosynthesis of peptidoglycan, the main component of the bacterial cell wall, not by targeting membrane-bound extracellular enzymes but at the cytoplasmic stage of biosynthesis by inhibiting Mur enzymes, which are essential for bacterial survival [21].…”

Section: Introductionmentioning

confidence: 99%

Modeling of Effectiveness of N3-Substituted Amidrazone Derivatives as Potential Agents against Gram-Positive Bacteria

Ćwiklińska-Jurkowska,

Paprocka,

Mwaura

et al. 2024

Molecules

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Prediction of the antibacterial activity of new chemical compounds is an important task, due to the growing problem of bacterial drug resistance. Generalized linear models (GLMs) were created using 85 amidrazone derivatives based on the results of antimicrobial activity tests, determined as the minimum inhibitory concentration (MIC) against Gram-positive bacteria: Staphylococcus aureus, Enterococcus faecalis, Micrococcus luteus, Nocardia corallina, and Mycobacterium smegmatis. For the analysis of compounds characterized by experimentally measured MIC values, we included physicochemical properties (e.g., molecular weight, number of hydrogen donors and acceptors, topological polar surface area, compound percentages of carbon, nitrogen, and oxygen, melting points, and lipophilicity) as potential predictors. The presence of R1 and R2 substituents, as well as interactions between melting temperature and R1 or R2 substituents, were also considered. The set of potential predictors also included possible biological effects (e.g., antibacterial, antituberculotic) of tested compounds calculated with the PASS (Prediction of Activity Spectra for Substances) program. Using GLMs with least absolute shrinkage and selection (LASSO), least-angle regression, and stepwise selection, statistically significant models with the optimal value of the adjusted determination coefficient and of seven fit criteria were chosen, e.g., Akaike’s information criterion. The most often selected variables were as follows: molecular weight, PASS_antieczematic, PASS_anti-inflam, squared melting temperature, PASS_antitumor, and experimental lipophilicity. Additionally, relevant to the bacterial strain, the interactions between melting temperature and R1 or R2 substituents were selected, indicating that the relationship between MIC and melting temperature depends on the type of R1 or R2 substituent.

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“…[17] Bacterial SRP is a ribonucleoprotein complex comprised of a 4.5S RNA and a Ffh protein, which along with its receptor protein (known as FtsY) mediates the co-translational translocation of nascent membrane and secretory proteins to the plasma membrane. [18][19][20][21][22] Two sequence-specific PNA molecules were designed to target the 4.5S non-coding RNA near the Ffh binding site. PNA1 was 9-mer, while PNA2 was 8-mer in length (referred to as PNA 9 and PNA 8 respectively in this paper (Figure 1A and Table S1).…”

Section: Introductionmentioning

confidence: 99%

“…In a previous study, we have reported PNA mediated inhibition of the bacterial Signal Recognition Particle (SRP) via inhibition of an essential RNA‐protein interaction [17] . Bacterial SRP is a ribonucleoprotein complex comprised of a 4.5S RNA and a Ffh protein, which along with its receptor protein (known as FtsY) mediates the co‐translational translocation of nascent membrane and secretory proteins to the plasma membrane [18–22] . Two sequence‐specific PNA molecules were designed to target the 4.5S non‐coding RNA near the Ffh binding site.…”

Section: Introductionmentioning

confidence: 99%

Effects of PNA Sequence and Target Site Selection on Function of a 4.5S Non‐Coding RNA

Saini,

Goel,

Ghosh

et al. 2024

ChemBioChem

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Peptide nucleic acid (PNA) based antisense strategy is a promising therapeutic approach to specifically inhibit target gene expression. However, unlike protein coding genes, identification of an ideal PNA binding site for non‐coding RNA is not straightforward. Here, we compare the inhibitory activities of PNA molecules that bind a non‐coding 4.5S RNA called SRP RNA, a key component of the bacterial signal recognition particle (SRP). A 9‐mer PNA (PNA9) complementary to the tetraloop region of the RNA was more potent in inhibiting its interaction with the SRP protein, compared to an 8‐mer PNA (PNA8) targeting a stem‐loop. PNA9, which contained a homo‐pyrimidine sequence could form a triplex with the complementary stretch of RNA in vitro as confirmed using a fluorescent derivative of PNA9 (F‐PNA13). The RNA‐PNA complex formation resulted in inhibition of SRP function with PNA9 and F‐PNA13, but not PNA8 highlighting the importance of target site selection. Surprisingly, F‐PNA13 which was more potent in inhibiting SRP function in vitro, showed weaker antibacterial activity compared to PNA9 likely due to poor cell penetration of the longer PNA. Our results underscore the importance of suitable target site selection and optimum PNA length to develop better antisense molecules against non‐coding RNA.

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Novel Antibacterial Targets in Protein Biogenesis Pathways

Cited by 5 publications

References 235 publications

In Vitro Microevolution and Co-Selection Assessment of Florfenicol Impact on Escherichia coli Resistance Development

In Vitro Microevolution and Co-Selection Assessment of Florfenicol Impact on Escherichia coli Resistance Development

Modeling of Effectiveness of N3-Substituted Amidrazone Derivatives as Potential Agents against Gram-Positive Bacteria

Effects of PNA Sequence and Target Site Selection on Function of a 4.5S Non‐Coding RNA

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