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Computational modelling of potential Zn-sensitive non-β-lactam inhibitors of imipenemase-1 (IMP-1)

Ayipo YO, Ahmad I, Alananzeh W, Lawal A, Patel H, Mordi MN

J Biomol Struct Dyn, 2023 Nov;41(19):10096-10116.
PMID: 36476097 DOI: 10.1080/07391102.2022.2153168

Antibiotic resistance (AR) remains one of the leading global health challenges, mostly implicated in disease-related deaths. The Enterobacteriaceae-producing metallo-β-lactamases (MBLs) are critically involved in AR pathogenesis through Zn-dependent catalytic destruction of β-lactam antibiotics, yet with limited successful clinical inhibitors. The efficacy of relevant broad-spectrum β-lactams including imipenem and meropenem are seriously challenged by their susceptibility to the Zn-dependent carbapenemase hydrolysis, as such, searching for alternatives remains imperative. In this study, computational molecular modelling and virtual screening methods were extensively applied to identify new putative Zn-sensitive broad-spectrum inhibitors of MBLs, specifically imipenemase-1 (IMP-1) from the IBScreen database. Three ligands, STOCK3S-30154, STOCK3S-30418 and STOCK3S-30514 selectively displayed stronger binding interactions with the enzymes compared to reference inhibitors, imipenem and meropenem. For instance, the ligands showed molecular docking scores of -9.450, -8.005 and -10.159 kcal/mol, and MM-GBSA values of -40.404, -31.902 and -33.680 kcal/mol respectively against the IMP-1. Whereas, imipenem and meropenem showed docking scores of -9.038 and -10.875 kcal/mol, and MM-GBSA of -31.184 and -32.330 kcal/mol respectively against the enzyme. The ligands demonstrated good thermodynamic stability and compactness in complexes with IMP-1 throughout the 100 ns molecular dynamics (MD) trajectories. Interestingly, their binding affinities and stabilities were significantly affected in contacts with the remodelled Zn-deficient IMP-1, indicating sensitivity to the carbapenemase active Zn site, however, with non-β-lactam scaffolds, tenable to resist catalytic hydrolysis. They displayed ideal drug-like ADMET properties, thus, representing putative Zn-sensitive non-β-lactam inhibitors of IMP-1 amenable for further experimental studies.

Matched MeSH terms: beta-Lactamase Inhibitors/pharmacology
Stigmasterol: An adjuvant for beta lactam antibiotics against beta-lactamase positive clinical isolates

Yenn TW, Arslan Khan M, Amiera Syuhada N, Chean Ring L, Ibrahim D, Tan WN

Steroids, 2017 Dec;128:68-71.
PMID: 29104098 DOI: 10.1016/j.steroids.2017.10.016

The emergence of beta lactamase producing bacterial strains eliminated the use of beta lactam antibiotics as chemotherapeutic alternative. Beta lactam antibiotics can be coupled with non-antibiotic adjuvants to combat these multidrug resistant strains. We study the synergistic antibiotic effect of stigmasterol as adjuvant of ampicillin against clinical isolates. Ampicillin was used in this study as a beta lactam antibiotic model. All test bacteria were beta lactamase producing clinical isolates. The combination showed significantly better antibiotic activity on all bacteria tested. The two test substances have synergistic antibiotic activity, and the effect was observed in both Gram positive and Gram negative bacteria. The synergistic antibiotic effect of stigmasterol and ampicillin was evident by the low fractional inhibitory concentration (FIC) index on Checkerboard Assay. The results suggest that the combination of ampicillin and stigmasterol acts additively in the treatment of infections caused by beta-lactamase producing pathogens. In bacterial growth reduction assay, ampicillin and stigmasterol alone exhibited very weak inhibitory effect on the bacterial growth, relative to ethanol control. Comparatively, combination of stigmasterol-ampicillin greatly reduced the colony counts at least by 98.7%. In conclusion, we found synergistic effects of stigmasterol and ampicillin against beta lactamase producing clinical isolates. This finding is important as it shows potential application of stigmasterol as an antibiotic adjuvant.

Matched MeSH terms: beta-Lactamase Inhibitors/pharmacology*; beta-Lactamase Inhibitors/chemistry
Fulltext Comparable outcomes for β-lactam/β-lactamase inhibitor combinations and carbapenems in definitive treatment of bloodstream infections caused by cefotaxime-resistant Escherichia coli or Klebsiella pneumoniae

Harris PN, Yin M, Jureen R, Chew J, Ali J, Paynter S, et al.

Antimicrob Resist Infect Control, 2015;4:14.
PMID: 25932324 DOI: 10.1186/s13756-015-0055-6

Extended-spectrum β-lactamase (ESBL) producing Enterobacteriaceae are often susceptible in vitro to β-lactam/β-lactamase inhibitor (BLBLI) combination antibiotics, but their use has been limited by concerns of clinical inefficacy. We aimed to compare outcomes between patients treated with BLBLIs and carbapenems for bloodstream infection (BSI) caused by cefotaxime non-susceptible (likely ESBL- or AmpC β-lactamase-producing) Escherichia coli and Klebsiella pneumoniae.

Matched MeSH terms: beta-Lactamase Inhibitors
Fulltext Design and Characterisation of Inhibitory Peptides against Bleg1_2478, an Evolutionary Divergent B3 Metallo-β-lactamase

Selvaraju G, Leow TC, Salleh AB, Normi YM

Molecules, 2020 Dec 09;25(24).
PMID: 33316879 DOI: 10.3390/molecules25245797

Previously, a hypothetical protein (HP) termed Bleg1_2437 (currently named Bleg1_2478) from Bacillus lehensis G1 was discovered to be an evolutionary divergent B3 subclass metallo-β-lactamase (MBL). Due to the scarcity of clinical inhibitors for B3 MBLs and the divergent nature of Bleg1_2478, this study aimed to design and characterise peptides as inhibitors against Bleg1_2478. Through in silico docking, RSWPWH and SSWWDR peptides with comparable binding energy to ampicillin were obtained. In vitro assay results showed RSWPWH and SSWWDR inhibited the activity of Bleg1_2478 by 50% at concentrations as low as 0.90 µM and 0.50 µM, respectively. At 10 µM of RSWPWH and 20 µM of SSWWDR, the activity of Bleg1_2478 was almost completely inhibited. Isothermal titration calorimetry (ITC) analyses showed slightly improved binding properties of the peptides compared to ampicillin. Docked peptide-protein complexes revealed that RSWPWH bound near the vicinity of the Bleg1_2478 active site while SSWWDR bound at the center of the active site itself. We postulate that the peptides caused the inhibition of Bleg1_2478 by reducing or blocking the accessibility of its active site from ampicillin, thus hampering its catalytic function.

Matched MeSH terms: beta-Lactamase Inhibitors/chemical synthesis*; beta-Lactamase Inhibitors/pharmacology; beta-Lactamase Inhibitors/chemistry*
Fulltext Antimicrobial susceptibility and virulence genes of clinical and environmental isolates of Pseudomonas aeruginosa

Liew SM, Rajasekaram G, Puthucheary SA, Chua KH

PeerJ, 2019;7:e6217.
PMID: 30697478 DOI: 10.7717/peerj.6217

Background: Pseudomonas aeruginosa is ubiquitous, has intrinsic antibiotic resistance mechanisms, and is associated with serious hospital-associated infections. It has evolved from being a burn wound infection into a major nosocomial threat. In this study, we compared and correlated the antimicrobial resistance, virulence traits and clonal relatedness between clinical and fresh water environmental isolates of P. aeruginosa.
Methods: 219 P. aeruginosa isolates were studied: (a) 105 clinical isolates from 1977 to 1985 (n = 52) and 2015 (n = 53), and (b) 114 environmental isolates from different fresh water sources. All isolates were subjected to ERIC-PCR typing, antimicrobial susceptibility testing and virulence factor genes screening.
Results: Clinical and environmental isolates of P. aeruginosa were genetically heterogenous, with only four clinical isolates showing 100% identical ERIC-PCR patterns to seven environmental isolates. Most of the clinical and environmental isolates were sensitive to almost all of the antipseudomonal drugs, except for ticarcillin/clavulanic acid. Increased resistant isolates was seen in 2015 compared to that of the archived isolates; four MDR strains were detected and all were retrieved in 2015. All clinical isolates retrieved from 1977 to 1985 were susceptible to ceftazidime and ciprofloxacin; but in comparison, the clinical isolates recovered in 2015 exhibited 9.4% resistance to ceftazidime and 5.7% to ciprofloxacin; a rise in resistance to imipenem (3.8% to 7.5%), piperacillin (9.6% to 11.3%) and amikacin (1.9% to 5.7%) and a slight drop in resistance rates to piperacillin/tazobactam (7.7% to 7.5%), ticarcillin/clavulanic acid (19.2% to 18.9%), meropenem (15.4% to 7.5%), doripenem (11.5% to 7.5%), gentamicin (7.7% to 7.5%) and netilmicin (7.7% to 7.5%). Environmental isolates were resistant to piperacillin/tazobactam (1.8%), ciprofloxacin (1.8%), piperacillin (4.4%) and carbapenems (doripenem 11.4%, meropenem 8.8% and imipenem 2.6%). Both clinical and environmental isolates showed high prevalence of virulence factor genes, but none were detected in 10 (9.5%) clinical and 18 (15.8%) environmental isolates. The exoT gene was not detected in any of the clinical isolates. Resistance to carbapenems (meropenem, doripenem and imipenem), β-lactamase inhibitors (ticarcillin/clavulanic acid and piperacillin/tazobactam), piperacillin, ceftazidime and ciprofloxacin was observed in some of the isolates without virulence factor genes. Five virulence-negative isolates were susceptible to all of the antimicrobials. Only one MDR strain harbored none of the virulence factor genes.
Conclusion: Over a period of 30 years, a rise in antipseudomonal drug resistance particularly to ceftazidime and ciprofloxacin was observed in two hospitals in Malaysia. The occurrence of resistant environmental isolates from densely populated areas is relevant and gives rise to collective anxiety to the community at large.

Matched MeSH terms: beta-Lactamase Inhibitors
Danger lurking in the "unknowns": structure-to-function studies of hypothetical protein Bleg1_2437 from Bacillus lehensis G1 alkaliphile revealed an evolutionary divergent B3 metallo-beta-lactamase

Tan SH, Normi YM, Leow AT, Salleh AB, Murad AM, Mahadi NM, et al.

J. Biochem., 2017 02 01;161(2):167-186.
PMID: 28175318 DOI: 10.1093/jb/mvw058

The effectiveness of β-lactam antibiotics as chemotherapeutic agents to treat bacterial infections is gradually threatened with the emergence of antibiotic resistance mechanism among pathogenic bacteria through the production metallo-β-lactamase (MBL). In this study, we discovered a novel hypothetical protein (HP) termed Bleg1_2437 from the genome of alkaliphilic Bacillus lehensis G1 which exhibited MBL-like properties of B3 subclass; but evolutionary divergent from other circulating B3 MBLs. Domain and sequence analysis of HP Bleg1_2437 revealed that it contains highly conserved Zn2+-binding residues such as H54, H56, D58, H59, H131 and H191, important for catalysis, similar with the subclass B3 of MBL. Built 3-D Bleg1_2437 structure exhibited an αββα sandwich layer similar to the well-conserved global topology of MBL superfamily. Other features include a ceiling and floor in the model which are important for accommodation and orientation of β-lactam antibiotics docked to the protein model showed interactions at varying degrees with residues in the binding pocket of Bleg1_2437. Hydrolysis activity towards several β-lactam antibiotics was proven through an in vitro assay using purified recombinant Bleg1_2437 protein. These findings highlight the presence of a clinically important and evolutionary divergent antibiotics-degrading enzyme within the pools of uncharacterized HPs.

Matched MeSH terms: beta-Lactamase Inhibitors/pharmacology
Fulltext Clostridium difficile Infection: clinico-epidemiological perspective

Syuhada, N., Azimatun, N.A., Alfizah, H., Tzar, M.N., Ramliza, R.

Medicine & Health, 2013;8(2):64-72.
MyJurnal

Clostridium difficile infection (CDI) causes mild to severe diarrhoea and pseudomembranous colitis in patients who had prior antibiotic exposure. Despite CDI being prevalent worldwide, its epidemiological data is scanty in Malaysia. This study aimed to determine the prevalence and incidence of CDI at Universiti Kebangsaan Malaysia Medical Centre (UKMMC). Stool specimens from 147-suspected CDI patients were obtained from 1 November 2011 until 31 October 2012. The presence of C. difficile toxin A and/or B were detected using a commercial immunochromatographic kit (Wampole™ Tox A/B Quik Chek). Surveillance data was collected from patients’ medical records to establish the demographic and clinical characteristics. The overall prevalence and incidence of CDI in UKMMC was 6.1% and 5.2 cases per 10 000 patient-days, respectively. Among nine CDI patients, 77.8% were males and 55.6% were Chinese. CDI was most common in medical wards (88.9%). The median age was 60 years and the median length of hospital stay was 13 days. Majority (88.9%) of CDI patients received antibiotics eight weeks prior to CDI. Penicillin-beta-lactamase inhibitors were the most common antecedent antibiotics. Five (55.6%) CDI patients received acid suppressant medications. The in-hospital mortality rate was 22.2%. In conclusion, the prevalence and incidence of CDI at UKMMC is relatively low and occurs sporadically.

Matched MeSH terms: beta-Lactamase Inhibitors
Fulltext Sputum bacteriology and in-vitro antibiotic susceptibility in hospitalized patients with community acquired pneumonia in a state tertiary-referral hospital – a retrospective study

Chin, Yow-Wen, Loh, Li-Cher, Wong, Thim-Fatt, Abdul Razak Muttalif

International e-Journal of Science, Medicine & Education, 2007;1(2):74-79.
MyJurnal

Introduction: To review the sputum bacteriology and its in-vitro antibiotic susceptibility in patients hospitalized with community-acquired pneumonia (CAP) in a state tertiary-referral Hospital (Penang hospital, Malaysia) in order to determine the most appropriate empiric antibiotics.
Methods: From September 2006 to May 2007, 68 immunocompetent adult patients [mean age: 52 years (range 16-89); 69% male] admitted to respiratory wards for CAP with positive sputum isolates within 48 hours of admission were retrospectively identified and reviewed.
Results: 62 isolates were Gram(-) bacilli (91%) & 6 were Gram(+) cocci (9%). The two commonest pathogens isolated were Pseudomonas aeruginosa (n=20) and Klebsiella pneumoniae (n=19) together constituted 57% of all positive isolates. Among the Pseudomonas isolates, 84.2% were fully sensitive to cefoperazone and cefoperazon/sulbactam; 95% to ceftazidime, cefepime, piperacillin/tazobactam, ciprofloxacin and amikacin, and 100% to gentamycin, netilmycin, imipenem and meropenem. Among the Klebsiella isolates, 5.3% were fully sensitive to ampicillin; 84.2% to amoxicillin, ampicllin/sulbactam, cefuroxime and ceftriazone; 89.5% to piperacillin/ tazobactam; 93.3% to cefoperazon/sulbactam and 100% sensitive to ceftazidime, cefepime, ciprofloxacin, all aminoglycosides and carbopenems.
Conclusion: In view of the high prevalence of respiratory Pseudomonas aeruginosa, ampicillin/ sulbactam, currently the most prescribed antibiotic to treat CAP in our respiratory wards, may not be the most appropriate empiric choice. Higher generation cephalosporins with or without beta-lactamase inhibitors, ciprofloxacin or carbapenem may be the more appropriate choices. The lack of information on patients’ premorbidities such as recent hospitalization and prior antibiotic exposure, limits the interpretation of our findings and may have biased our results towards higher rates of Gram negative organisms.

Matched MeSH terms: beta-Lactamase Inhibitors