BACKGROUND: Macrolides inhibit the growth of bacterial cells by preventing the elongation of polypeptides during protein biosynthesis and includes natural, synthetic, and semisynthetic products. This occurs by blocking the passage of the polypeptide chain as macrolides bind at the nascent peptide exit tunnel.
OBJECTIVE: Recent data of ribosome profiling via ribo-seq further proves that other than blocking the polypeptide chain, macrolides are also able to affect the synthesis of individual proteins. Thus, this shows that the mode of action of macrolides is more complex than we initially thought. Since the discovery of macrolides in the 1950s, they have been widely used in veterinary, agriculture, and medicine. Due to misuse and overuse of antibiotics; bacteria have acquired resistance against them. Hence, it is of utmost importance for us to fully understand the mode of action of macrolides as well as the mechanism of resistance against macrolides to mitigate the antibiotic resistance issues.
BACKGROUND: With a better understanding on the mode of actions of macrolides, chemical modifications can be performed to improve its potency. Furthermore, the complete detailed understanding of the mode of action of macrolides remained vague as new findings challenged the theory that was already in existence - due to this obscurity, research into macrolides\' mode of action continues up to this day.
CONCLUSIONS: In this review, we present an overview of macrolide antibiotics with the emphasis on the latest knowledge regarding the mode of action of macrolides and mechanism of resistance employed in bacteria against macrolides.

The emergence and dissemination of antibiotic resistance genes (ARGs) in the ecosystem are global public health concerns. One Health emphasizes the interconnectivity between different habitats and seeks to optimize animal, human, and environmental health. However, information on the dissemination of antibiotic resistance genes (ARGs) within complex microbiomes in natural habitats is scarce. We investigated the prevalence of antibiotic resistant bacteria (ARB) and the spread of ARGs in intensive bullfrog (Rana catesbeiana) farms in the Shantou area of China. Antibiotic susceptibilities of 361 strains, combined with microbiome analyses, revealed Escherichia coli, Edwardsiella tarda, Citrobacter and Klebsiella sp. as prevalent multidrug resistant bacteria on these farms. Whole genome sequencing of 95 ARB identified 250 large plasmids that harbored a wide range of ARGs. Plasmid sequences and sediment metagenomes revealed an abundance of tetA, sul1, and aph(3″)-Ib ARGs. Notably, antibiotic resistance (against 15 antibiotics) highly correlated with plasmid-borne rather than chromosome-borne ARGs. Based on sequence similarities, most plasmids (62%) fell into 32 distinct groups, indicating a potential for horizontal plasmid transfer (HPT) within the frog farm microbiome. HPT was confirmed in inter- and intra-species conjugation experiments. Furthermore, identical mobile ARGs, flanked by mobile genetic elements (MGEs), were found in different locations on the same plasmid, or on different plasmids residing in the same or different hosts. Our results suggest a synergy between MGEs and HPT to facilitate ARGs dissemination in frog farms. Mining public databases retrieved similar plasmids from different bacterial species found in other environmental niches globally. Our findings underscore the importance of HPT in mediating the spread of ARGs in frog farms and other microbiomes of the ecosystem.

This study explores the challenge of antimicrobial resistance by investigating the utilization of zinc oxide (ZnO) and copper oxide (Cu2O) nanoparticles (NPs) to combat antibiotic-resistant bacteria in wastewater treatment plants (WWTPs). The synthesized metal oxide NPs underwent thorough characterization through various analytical techniques, confirming their nanoparticulate nature. Electronic absorption and X-ray diffraction (XRD) analyses revealed successful reduction processes and crystalline properties, respectively. Fourier transform infrared spectroscopy (FTIR) results indicated the stabilization of nanoparticles in solution. Scanning electron microscopy (SEM) observations revealed well-defined spherical and flower-like morphologies for the zinc and copper oxide nanoparticles, with sizes approximately ranging from 50 nm to 25 nm Notably, the synthesized nanoparticles exhibited heightened efficacy in impeding biofilm formation, with zinc oxide NPs displaying superior antibacterial activity compared to copper. These findings suggest the promising potential of these nanoparticles in controlling antibiotic-resistant organisms, even following WWTP treatment processes. This research contributes to the ongoing advancements in nanotechnology aimed at combating antibiotic resistance, offering new prospects for the development of effective wastewater treatment strategies.

The transmission of antibiotic resistance genes (ARGs) and the propagation of antibiotic resistant bacteria (ARB) threaten public health security and human health, and greener and more efficient disinfection technologies are expected to be discovered for wastewater treatment. In this study, natural pyrite and ascorbic acid (AA) were proposed as environmental-friendly activator and reductant for periodate (PI) activation to inactivate ARB. The disinfection treatment of PI/pyrite/AA system could inactivate 5.62 log ARB within 30 min, and the lower pH and higher PI and natural pyrite dosage could further boost the disinfection efficiency. The 1O2 and SO4•- were demonstrated to be crucial for the inactivation of ARB in PI/pyrite/AA system. The disinfection process destroyed the morphological structure of ARB, inducing oxidative stress and stimulating the antioxidant system. The PI/pyrite/AA system effectively reduced the intracellular and extracellular DNA concentration and ARGs abundance, inhibiting the propagation of ARGs. The presence of AA facilitated the activation of PI with natural pyrite and significantly increased the concentration of Fe2+ in solution. The reusability of natural pyrite, the safety of the disinfection by-products and the inhibition of ARB regeneration indicated the application potential of PI/pyrite/AA system in wastewater disinfection.

Antimicrobial resistance (AMR) is one of the main global health challenges. Anaerobic digestion (AD) can significantly reduce the burden of antibiotic resistance genes (ARGs) in animal manures. However, the reduction is often incomplete. The agronomic use of digestates requires assessments of their effects on soil ARGs. The objective of this study was to assess the effect of digestate on the abundance of ARGs and mobile genetic elements (MGEs) in the rhizosphere of ryegrass (Lolium perenne L.) and to determine whether half-dose replacement of digestate with urea (combined fertilizer) can be implemented as a safer approach while maintaining a similar biomass production. A greenhouse assay was conducted during 190 days under a completely randomized design with two experimental factors: fertilizer type (unfertilized control and fertilized treatments with equal N dose: digestate, urea and combined fertilizer) and sampling date (16 and 148 days after the last application). The results indicated that the digestate significantly increased the abundance of clinical class 1 integrons (intI1 gene) relative to the unfertilized control at both sampling dates (P < 0.05), while the combined fertilizer only increased them at the first sampling. Sixteen days after completing the fertilization scheme only the combined fertilizer and urea significantly increased the biomass production relative to the control (P < 0.05). Additionally, by the end of the assay, the combined fertilizer showed significantly lower levels of the macrolide-resistance gene ermB than digestate and a cumulative biomass similar to urea or digestate. Overall, the combined fertilizer can alleviate the burden of integrons and ermB while simultaneously improving biomass production.

The dynamics of the composition and antibiotic resistance of the fecal coliform bacteria (FCB) in a typical wastewater treatment plant (WWTP) were investigated concerning the seasonal changes. Results showed that WWTP could remove the FCB concentration by 3∼5 logs within the effluent of 104∼105 CFU/L, but the antibiotic resistant rate of FCB species increased significantly after WWTP. The dominant FCB changed from Escherichia coli in the influent (∼73.0%) to Klebsiella pneumoniae in the effluent (∼53.3%) after WWTP, where the Escherichia coli was removed the most, while Klebsiella pneumoniae was the most persistent. The secondary tank removed the most of FCB (by 3∼4 logs) compared to other processes, but increased all the concerned antibiotic resistant rate. The potential super bugs of FCB community showing resistance to all the target antibiotics were selected in the biological treatment unit of WWTP. The FCB showed the highest multiple antibiotic resistance (92.9%) in total which even increased to 100% in the effluent. Klebsiella has the highest antibiotic resistant rate in FCB, with a multiple antibiotic resistance rate of 98.4%. These indicated that the Klebsiella pneumoniae not just Escherichia coli should be specially emphasized after WWTP concerning the health risk associated with FCB community.

In this study, the activation of peroxydisulfate (PS) by K2FeO4-activation biochar (KFeB) and acid-picking K2FeO4-activation biochar (AKFeB) was investigated to reveal the mechanism differences between iron site and graphitic structure in sulfadiazine (SDZ) degradation and ARB inactivation, respectively. KFeB/PS and AKFeB/PS systems had similar degradation property towards SDZ, but only KFeB/PS system showed excellent bactericidal property. The mechanism study demonstrated that dissolved SDZ was degraded through electron transfer pathway mediated by graphitic structure, while suspended ARB was inactivated through free radicals generated by iron-activated PS, accompanied by excellent removal on antibiotic resistance genes (ARGs). The significant decrease in conjugative transfer frequency indicated the reduced horizontal gene transfer risk of ARGs after treatment with KFeB/PS system. Transcriptome data suggested that membrane protein channel disruption and adenosine triphosphate synthesis inhibition were key reasons for conjugative transfer frequency reduction. Continuous flow reactor of KFeB/PS system can efficiently remove antibiotics and ARB, implying the potential application in practical wastewater purification. In conclusion, this study provides novel insights for classified and collaborative control of antibiotics and ARB by carbon-based catalysts driven persulfate advanced oxidation technology.

With the global concerns on antibiotic resistance (AR) as a public health issue, it is pivotal to have data exchange platforms for studies on antibiotic resistant bacteria (ARB) and antibiotic resistance genes (ARGs) in the environment. For this purpose, the NORMAN Association is hosting the NORMAN ARB&ARG database, which was developed within the European project ANSWER. The present article provides an overview on the database functionalities, the extraction and the contribution of data to the database. In this study, AR data from three studies from China and Nepal were extracted and imported into the NORMAN ARB&ARG in addition to the existing AR data from 11 studies (mainly European studies) on the database. This feasibility study demonstrates how the scientific community can share their data on AR to generate an international evidence base to inform AR mitigation strategies. The open and FAIR data are of high potential relevance for regulatory applications, including the development of emission limit values / environmental quality standards in relation to AR. The growth in sharing of data and analytical methods will foster collaboration on risk management of AR worldwide, and facilitate the harmonization in the effort for identification and surveillance of critical hotspots of AR. The NORMAN ARB&ARG database is publicly available at: https://www.norman-network.com/nds/bacteria/.

Antibiotic resistance (AR) is considered one of the greatest global threats in the current century, which can only be overcome if all interconnected areas of humans, animals and the environment are taken into account as part of the One Health concept proposed by the World Health Organization (WHO). Water and wastewater are among the most important environmental media of AR sources, where the phenomena are generally non-linear. Therefore, the aim of this study was to investigate the application of machine learning-based methods (MLMs) to solve AR-induced problems in water and wastewater. For this purpose, most relevant databases were searched in the period between 1987 and 2023 to systematically analyze and categorize the applications. Accordingly, the results showed that out of 12 applications, 11 (91.6%) were for shallow learning and 1 (8.3%) for deep learning. In shallow learning category, n = 6, 50% of the applications were regression and n = 4, 33.3% were classification, mainly using artificial neural networks, decision trees and Bayesian methods for the following objectives: Predicting the survival of antibiotic-resistant bacteria (ARB), determining the order of influencing parameters on AR-based scores, and identifying the major sources of antibiotic resistance genes (ARGs). In addition, only one study (8.3%) was found for clustering and no study for association. Surprisingly, deep learning had been used in only one study (8.3%) to predict ARGs sequences. Therefore, working on the knowledge gaps of AR, especially using clustering, association and deep learning methods, would be a promising option to analyze more aspects of the related problems. However, there is still a long way to go to consider and apply MLMs as unique approaches to study different aspects of AR in water and wastewater.

To mitigate the environmental risks posed by the accumulation of antibiotic mycelial dregs (AMDs), this study first attempted over 200 tons of mass production fermentation (MP) using tylosin and spectinomycin mycelial dregs alongside pilot-scale fermentation (PS) for comparison, utilizing the integrated-omics and qPCR approaches. Co-fermentation results showed that both antibiotics were effectively removed in all treatments, with an average removal rate of 92%. Antibiotic resistance gene (ARG)-related metabolic pathways showed that rapid degradation of antibiotics was associated with enzymes that inactivate macrolides and aminoglycosides (e.g., K06979, K07027, K05593). Interestingly, MP fermentations with optimized conditions had more efficient ARGs removal because homogenization permitted faster microbial succession, with more stable removal of antibiotic resistant bacteria and mobile genetic elements. Moreover, Bacillus reached 75% and secreted antioxidant enzymes that might inhibit horizontal gene transfer of ARGs. The findings confirmed the advantages of MP fermentation and provided a scientific basis for other AMDs.